Substituted pyrrolopyridines as jak inhibitors

ABSTRACT

The present invention relates to new pyrrolopyridine compounds having the structures of Formula (I)-(IV), wherein the R groups, A, B, C, D and n are as defined in the detailed description, and compositions and their application as pharmaceuticals for the treatment of disease. 
     
       
         
         
             
             
         
       
     
     Methods of inhibition of JAK kinase activity in a human or animal subject are also provided for the treatment diseases such as pruritus, alopecia, androgenetic alopecia, alopecia areata, vitiligo and psoriasis.

CLAIM OF PRIORITY

This Divisional application claims the benefit of priority to U.S.Non-provisional application Ser. No. 16/866,182, filed May 4, 2020,which claims the benefit of priority to U.S. Provisional Application No.62/842,197, filed May 2, 2019, which are incorporated hereinby referencein their entirety.

SUMMARY

Embodiments herein are directed to having the structures of Formulas(I)-(IV), or a derivative thereof, where the R groups, ring labels, andn values are defined herein:

Disclosed herein are new pyrrolopyridine compounds and compositions andtheir application as pharmaceuticals for the treatment of disease.Methods of inhibition of JAK kinase activity in a human or animalsubject are also provided for the treatment of JAK-mediated conditions.

The Janus Kinases (JAKs) are a subgroup of non-receptor tyrosine kinasesthat are essential to transducing signals originating from type I andtype II cytokine receptors and whose enzymatic activity is essential forthe biological activity of the cytokines. The JAK kinase family consistsof four family members: JAK1, JAK2, JAK3 and Tyk2, and these kinases arecentral to the regulation of cytokine signaling in the immune system, aswell as more broadly in other tissues. The kinase activity of JAKs isdirected towards the JAKs themselves, the intracellular portion of thecytokine receptor, and several other substrates including the members ofthe STAT family of transcription factors. The STATs (STAT1 throughSTATE) have specific and distinct effects on gene transcription innumerous cell types, including immune cells, and are critical inprocesses such as cell proliferation and differentiation. Due to thebroad role these kinases have in immunity and inflammation, numeroussmall molecule drugs have been developed to intervene in diseases whereJAK kinase signaling contributes to disease. Initially, these drugs weredeveloped for systemic administration for the prevention of organtransplant rejection. Subsequently they have been developed as potentialtherapies for hematologic malignancies, and autoimmune and inflammatorydiseases including rheumatoid arthritis, ulcerative colitis,inflammatory bowel disease, ankylosing spondylitis, psoriasis, atopicdermatitis, alopecia disorders, and vitiligo, to name a few. Morerecently, due to the hematologic, immunosuppressive and metabolictoxicities associated with systemic inhibition of the JAK kinases, localdelivery of these inhibitors as topical agents has been described. Theseinclude alopecia areata, atopic dermatitis, vitiligo, psoriasis,inflammatory bowel diseases, and dry eye, among others. This documentdescribes compounds that have excellent oral and topical bioavailabilityand are useful for systemic autoimmune disease, as well as compoundsdesigned to have limited stability and hence limited systemic exposure,therefore, be best suited for local (e.g., topical) drug delivery.

Signal transduction of cytokine receptors activated by cytokines hasbeen shown to occur through JAK kinases associated with receptorcytoplasmic domains. Receptor stimulation results in the activation ofthe JAKs and subsequent phosphorylation of the cytoplasmic domain of theassociated receptor chains. This creates an SH2-binding domain, whichserves to recruit the latent cytoplasmic transcription factors known asSTATs (Signal Transducer and Activator of Transcription). While bound tothe phosphorylated cytokine receptors, the STATs themselves becomephosphorylated on tyrosine residues—which leads to SH2-domain mediatedhomo- and hetero-dimer formation and translocation to the nucleus. Oncethere, these proteins induce the transcription of genes associated withactivation of the original cytokine receptor. This sequence of events(STAT protein phosphorylation in minutes, and STAT-induced genetranscription in hours) are both amenable to characterizing the cellularpotency of compounds and informing structure-activity relationships.

DETAILED DESCRIPTION

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particularprocesses, formulations, compositions, or methodologies described, asthese may vary. It is also to be understood that the terminology used inthe description is for the purpose of describing the particular versionsor embodiments only and is not intended to limit the scope ofembodiments herein which will be limited only by the appended claims.Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art. Although any methods and materials similar or equivalent tothose described herein can be used in the practice or testing ofembodiments of embodiments herein, the preferred methods, devices, andmaterials are now described. All publications mentioned herein areincorporated by reference in their entirety. Nothing herein is to beconstrued as an admission that embodiments herein are not entitled toantedate such disclosure by virtue of prior invention.

Definitions

It must also be noted that as used herein and in the appended claims,the singular forms “a,” “an,” and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, reference toa “JAK inhibitor” is a reference to one or more JAK inhibitors andequivalents thereof known to those skilled in the art, and so forth.

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean plus or minus 10% of thenumerical value of the number with which it is being used. Therefore,about 50% means in the range of 45%-55%.

The transitional term “comprising,” which is synonymous with“including,” “containing,” or “characterized by,” is inclusive oropen-ended and does not exclude additional, unrecited elements or methodsteps. In embodiments or claims where the term “comprising” is used asthe transition phrase, such embodiments can also be envisioned withreplacement of the term “comprising” with the terms “consisting of” or“consisting essentially of.”

As used herein, the term “consists of” or “consisting of” means that thepharmaceutical composition, composition or the method includes only theelements, steps, or ingredients specifically recited in the particularclaimed embodiment or claim.

As used herein, the term “consisting essentially of” or “consistsessentially of” means that the pharmaceutical composition, or the methodincludes only the elements, steps or ingredients specifically recited inthe particular claimed embodiment or claim and may optionally includeadditional elements, steps or ingredients that do not materially affectthe basic and novel characteristics of the particular embodiment orclaim. For example, the only active ingredient(s) in the composition ormethod that treats the specified condition (e.g., nutrient depletion) isthe specifically recited therapeutic(s) in the particular embodiment orclaim.

As used herein, two embodiments are “mutually exclusive” when one isdefined to be something which is different from the other. For example,an embodiment wherein two groups combine to form a cycloalkyl ismutually exclusive with an embodiment in which one group is ethyl theother group is hydrogen. Similarly, an embodiment wherein one group isCH₂ is mutually exclusive with an embodiment wherein the same group isNH.

As used herein, the term “a derivative thereof” refers to a saltthereof, a pharmaceutically acceptable salt thereof, an ester thereof, afree acid form thereof, a free base form thereof, a solvate thereof, aco-crystal thereof, a deuterated derivative thereof, a hydrate thereof,an N-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorphthereof, a stereoisomer thereof, a geometric isomer thereof, a tautomerthereof, a mixture of tautomers thereof, an enantiomer thereof, adiastereomer thereof, a racemate thereof, a mixture of stereoisomersthereof, an isotope thereof (e.g., tritium, deuterium), or a combinationthereof.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt prepared from a base or acid which is acceptable for administrationto a patient, such as a mammal. The term “pharmaceutically acceptablesalts” embraces salts commonly used to form alkali metal salts and toform addition salts of free acids or free bases. The nature of the saltis not critical, provided that it is pharmaceutically-acceptable. Suchsalts can be derived from pharmaceutically-acceptable inorganic ororganic bases and from pharmaceutically-acceptable inorganic or organicacids.

The term “gut-restricted” or “gut-restricted compound,” as used herein,refers to a compound that preferentially acts within the intestinallumen without reaching sufficient exposure in the systemic circulationto illicit a significant pharmacologic response. Without intending to bebound by theory, this results in enhanced safety of the molecule as aconsequence of minimizing systemic exposure of the pharmacologicalagent, or its metabolites, to cells, tissues and organs/organ systemsunrelated to disease treatment.

The term “improve” is used to convey that the compounds of embodimentsherein change either the appearance, form, characteristics and/or thephysical attributes of the tissue to which it is being provided, appliedor administered.

The term “inhibit” means to limit, prevent or block the action orfunction of a target enzyme and/or, to prevent, alleviate or eliminatethe onset of one or more symptoms associated with a disease, conditionor disorder, or to prevent, alleviate or eliminate a disease, conditionor disorder.

When ranges of values are disclosed, and the notation “from n1 . . . ton2” or “between n1 . . . and n2” is used, where n1 and n2 are thenumbers, then unless otherwise specified, this notation is intended toinclude the numbers themselves and the range between them. This rangemay be integral or continuous between and including the end values. Byway of example, the range “from 2 to 6 carbons” is intended to includetwo, three, four, five, and six carbons, since carbons come in integerunits. Compare, by way of example, the range “from 1 to 3 μM(micromolar),” which is intended to include 1 μM, 3 μM, and everythingin between to any number of significant figures (e.g., 1.255 μM, 2.1 μM,2.9999 μM, etc.).

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycle, or any other moiety were the atom attached to the carbonylis carbon. An “acetyl” group refers to a —C(O)CH₃ group. An“alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached tothe parent molecular moiety through a carbonyl group. Examples of suchgroups include methylcarbonyl and ethylcarbonyl. Examples of acyl groupsinclude formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkenyl will comprise from 2 to 6 carbon atoms. Theterm “alkenylene” refers to a carbon-carbon double bond system attachedat two or more positions such as ethenylene [(—CH═CH—),(—C::C—)].Examples of suitable alkenyl radicals include ethenyl, propenyl,2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwisespecified, the term “alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term alkyl is as defined below.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,and the like.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical containing from 1 to 20carbon atoms. In certain embodiments, said alkyl will comprise from 1 to10 carbon atoms. In further embodiments, said alkyl will comprise from 1to 8 carbon atoms. Alkyl groups may be optionally substituted as definedherein.

Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl,octyl, nonyl and the like. The term “alkylene,” as used herein, alone orin combination, refers to a saturated aliphatic group derived from astraight or branched chain saturated hydrocarbon attached at two or morepositions, such as methylene (—CH₂—). Unless otherwise specified, theterm “alkyl” may include “alkylene” groups.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylidene,” as used herein, alone or in combination, refersto an alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) radical wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof suitable alkyl thioether radicals include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl,” as used herein, alone or in combination, refers to astraight-chain or branched chain hydrocarbon radical having one or moretriple bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkynyl comprises from 2 to 6 carbon atoms. In furtherembodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term“alkynylene” refers to a carbon-carbon triple bond attached at twopositions such as ethynylene (—C:::C—, —C≡C—

Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl,butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, andthe like. Unless otherwise specified, the term “alkynyl” may include“alkynylene” groups.

The terms “amido” and “carbamoyl,” as used herein, alone or incombination, refer to an amino group as described below attached to theparent molecular moiety through a carbonyl group, or vice versa. Theterm “C-amido” as used herein, alone or in combination, refers to a—C(O)N(RR′) group with R and R′ as defined herein or as defined by thespecifically enumerated “R” groups designated. The term “N-amido” asused herein, alone or in combination, refers to a RC(O)NH(R′)— group,with R and R′ as defined herein or as defined by the specificallyenumerated “R” groups designated. The term “acylamino” as used herein,alone or in combination, embraces an acyl group attached to the parentmoiety through an amino group. An example of an “acylamino” group isacetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently chosen from hydrogen, alkyl,acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl,any of which may themselves be optionally substituted. Additionally, Rand R′ may combine to form heterocycloalkyl, either of which may beoptionally substituted.

The term “aryl,” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch polycyclic ring systems are fused together. The term “aryl”embraces aromatic groups such as phenyl, naphthyl, anthracenyl, andphenanthryl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein,alone or in combination, refers to an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl,phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent radical C₆H₄═ derived from benzene. Examplesinclude benzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers toan ester of carbamic acid (—NHCOO—) which may be attached to the parentmolecular moiety from either the nitrogen or acid end, and which may beoptionally substituted as defined herein.

The term “O-carbamyl” as used herein, alone or in combination, refers toa —OC(O)NRR′, group-with R and R′ as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers toa ROC(O)NR′— group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy,” as used herein, refers to —C(O)OH orthe corresponding “carboxylate” anion, such as is in a carboxylic acidsalt. An “O-carboxy” group refers to a RC(O)O— group, where R is asdefined herein. A “C-carboxy” group refers to a —C(O)OR groups where Ris as defined herein.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes (e.g.,tritium, deuterium) of the structures depicted.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein,alone or in combination, refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moietycontains from 3 to 12 carbon atom ring members and which may optionallybe a benzo fused ring system which is optionally substituted as definedherein. In certain embodiments, said cycloalkyl will comprise from 5 to7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl,indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and thelike. “Bicyclic” and “tricyclic” as used herein are intended to includeboth fused ring systems, such as decahydronaphthalene,octahydronaphthalene as well as the multicyclic (multicentered)saturated or partially unsaturated type. The latter type of isomer isexemplified in general by, bicyclo[1,1,1]pentane, camphor, adamantane,and bicyclo[3,2,1]octane.

The term “ester,” as used herein, alone or in combination, refers to acarboxy group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, refers to anoxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the radical. Dihalo and polyhaloalkyl radicals may have two ormore of the same halo atoms or a combination of different halo radicals.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene (—CFH—),difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and the like.

The term “halocycloalkyl” as used herein, alone or in combination,refers to a cycloalkyl radical having the meaning as defined abovewherein one or more hydrogens are replaced with a halogen. Specificallyembraced are monohalocycloalkyl, dihalocycloalkyl and polyhalochaloalkylradicals. A monohaloalkyl radical, for one example, may have an iodo,bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. Examples of haloalkyl radicalsinclude fluorocyclopropyl, difluorocyclopropyl, fluorocyclobutyl,chlorocyclobutyl, and chlorocyclopentyl.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or combinations thereof, fullysaturated or containing from 1 to 3 degrees of unsaturation, consistingof the stated number of carbon atoms and from one to three heteroatomschosen from N, O, and S, and wherein the N and S atoms may optionally beoxidized and the N heteroatom may optionally be quaternized. Theheteroatom(s) may be placed at any interior position of the heteroalkylgroup. Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃.

The term “heteroaryl,” as used herein, alone or in combination, refersto a 3 to 15 membered unsaturated heteromonocyclic ring, or a fusedmonocyclic, bicyclic, or tricyclic ring system in which at least one ofthe fused rings is aromatic, which contains at least one atom chosenfrom N, O, and S. In certain embodiments, said heteroaryl will comprisefrom 1 to 4 heteroatoms as ring members. In further embodiments, saidheteroaryl will comprise from 1 to 2 heteroatoms as ring members. Incertain embodiments, said heteroaryl will comprise from 5 to 7 atoms.The term also embraces fused polycyclic groups wherein heterocyclicrings are fused with aryl rings, wherein heteroaryl rings are fused withother heteroaryl rings, wherein heteroaryl rings are fused withheterocycloalkyl rings, or wherein heteroaryl rings are fused withcycloalkyl rings. Examples of heteroaryl groups include pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl,quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl,benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl,tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl,thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplarytricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyland the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated (but nonaromatic)monocyclic, bicyclic, or tricyclic heterocyclic group containing atleast one heteroatom as a ring member, wherein each said heteroatom maybe independently chosen from nitrogen, oxygen, and sulfur. In certainembodiments, said hetercycloalkyl will comprise from 1 to 4 heteroatomsas ring members. In further embodiments, said hetercycloalkyl willcomprise from 1 to 2 heteroatoms as ring members. In certainembodiments, said hetercycloalkyl will comprise from 3 to 8 ring membersin each ring. In further embodiments, said hetercycloalkyl will comprisefrom 3 to 7 ring members in each ring. In yet further embodiments, saidhetercycloalkyl will comprise from 5 to 6 ring members in each ring.“Heterocycloalkyl” and “heterocycle” are intended to include sulfones,sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclicfused and benzo fused ring systems; additionally, both terms alsoinclude systems where a heterocycle ring is fused to an aryl group, asdefined herein, or an additional heterocycle group. Examples ofheterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl,dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl,dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl,benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl,pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and thelike. The heterocycle groups may be optionally substituted unlessspecifically prohibited.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers to—OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group.

The term “imino,” as used herein, alone or in combination, refers to═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refersto ═N(OH) and ═N—O—.

The phrase “in the main chain” refers to the longest contiguous oradjacent chain of carbon atoms starting at the point of attachment of agroup to the compounds of any one of the formulas disclosed herein.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently selected from carbon, nitrogen, oxygen andsulfur.

The term “lower alkyl,” as used herein, alone or in a combination, wherenot otherwise specifically defined, means containing from 1 to andincluding 6 carbon atoms (i.e., C₁-C₆ alkyl).

The term “lower aryl,” as used herein, alone or in combination, meansphenyl or naphthyl, either of which may be optionally substituted asprovided.

The term “lower heteroaryl,” as used herein, alone or in combination,means either 1) monocyclic heteroaryl comprising five or six ringmembers, of which between one and four said members may be heteroatomschosen from N, O, and S, or 2) bicyclic heteroaryl, wherein each of thefused rings comprises five or six ring members, comprising between themone to four heteroatoms chosen from N, O, and S.

The term “lower cycloalkyl,” as used herein, alone or in combination,means a monocyclic cycloalkyl having between three and six ring members(i.e., C₃-C₆ cycloalkyl). Lower cycloalkyls may be unsaturated. Examplesof lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

The term “lower heterocycloalkyl,” as used herein, alone or incombination, means a monocyclic heterocycloalkyl having between four andsix ring members, of which between one and four may be heteroatomschosen from N, O, and S (i.e., C₃-C₆ heterocycloalkyl). Examples oflower heterocycloalkyls include oxetane, azetidiene, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, andmorpholinyl. Lower heterocycloalkyls may be unsaturated.

The term “lower amino,” as used herein, alone or in combination, refersto —NRR′, wherein R and R′ are independently chosen from hydrogen andlower alkyl, either of which may be optionally substituted.

The term “mercaptyl” as used herein, alone or in combination, refers toan RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in combination, refers to—NO₂.

As used herein, an “N-oxide” is formed from the tertiary basic amines orimines present in the molecule, using a convenient oxidizing agent.

The terms “oxy” or “oxa,” as used herein, alone or in combination, referto —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The term “substantially free” as used herein, alone or in combination,refers to a compound which is free from all other compounds within thelimits of detection as measured by any means including nuclear magneticresonance (NMR), gas chromatography/mass spectroscopy (GC/MS), or liquidchromatography/mass spectroscopy (LC/MS).

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer the —SO₃H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—S(O)₂—.

The term “N-sulfonamido” refers to a RS(═O)₂NR′— group with R and R′ asdefined herein.

The term “S-sulfonamido” refers to a —S(═O)₂NRR′, group, with R and R′as defined herein.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl—C(S)H and in combination is a —C(S)— group.

The term “N-thiocarbamyl” refers to an ROC(S)NR′— group, with R and R′as defined herein.

The term “O-thiocarbamyl” refers to a —OC(S)NRR′, group with R and R′ asdefined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X₃CS(O)₂NR— group withX is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X₃CS(O)₂— group where X isa halogen.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

The term “trisubstituted silyl,” as used herein, alone or incombination, refers to a silicone group substituted at its three freevalences with groups as listed herein under the definition of amino.Examples include trimethysilyl, tert-butyldimethylsilyl, triphenylsilyland the like.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that said groupis absent.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H,pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Wherestructurally feasible, two substituents may be joined together to form afused five-, six-, or seven-membered carbocyclic or heterocyclic ringconsisting of zero to three heteroatoms, for example formingmethylenedioxy or ethylenedioxy. An optionally substituted group may beunsubstituted (e.g., —CH₂CH₃), fully substituted (e.g., —CF₂CF₃),monosubstituted (e.g., —CH₂CH₂F) or substituted at a level anywherein-between fully substituted and monosubstituted (e.g., —CH₂CF₃). Wheresubstituents are recited without qualification as to substitution, bothsubstituted and unsubstituted forms are encompassed. Where a substituentis qualified as “substituted,” the substituted form is specificallyintended. Additionally, different sets of optional substituents to aparticular moiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety chosen fromhydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl andheterocycloalkyl, any of which may be optionally substituted. Such R andR′ groups should be understood to be optionally substituted as definedherein. Whether an R group has a number designation or not, every Rgroup, including R, R′ and Rn where n=(1, 2, 3, . . . n), everysubstituent, and every term should be understood to be independent ofevery other in terms of selection from a group. Should any variable,substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more thanone time in a formula or generic structure, its definition at eachoccurrence is independent of the definition at every other occurrence.Those of skill in the art will further recognize that certain groups maybe attached to a parent molecule or may occupy a position in a chain ofelements from either end as written. For example, an unsymmetrical groupsuch as —C(O)N(R)— may be attached to the parent moiety at either thecarbon or the nitrogen.

Stereogenic centers exist in the compounds disclosed herein. Thesecenters are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the stereogenic center. It shouldbe understood that the invention encompasses all stereoisomeric forms,including diastereomeric, enantiomeric, and epimeric forms, as well asd-isomers and 1-isomers, and mixtures thereof. Individual stereoisomersof compounds can be prepared synthetically from commercially availablestarting materials which contain defined stereochemical configurationsor by separation of mixtures of stereoisomeric products by conversion toa mixture of diastereomers followed by separation or recrystallization,chromatographic techniques, direct separation of stereoisomers by chiralchromatographic columns, or any other appropriate method known in theart. Starting compounds of particular configurations are eithercommercially available or can be made and resolved by techniques knownin the art. Additionally, the compounds disclosed herein may exist asgeometric isomers. The present invention includes all cis, trans, syn,anti, endo, exo, entgegen (E), and zusammen (Z) isomers as well as theappropriate mixtures thereof. Additionally, compounds may exist astautomers; all tautomeric isomers are provided by this invention.Additionally, the compounds disclosed herein can exist in unsolvated aswell as solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder,”“syndrome,” and “condition” (as in medical condition), in that allreflect an abnormal condition of the human or animal body or of one ofits parts that impairs normal functioning, is typically manifested bydistinguishing signs and symptoms, and causes the human or animal tohave a reduced duration or quality of life.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a condition or disorder described in thepresent disclosure. Such administration encompasses co-administration ofthese therapeutic agents in a substantially simultaneous manner, such asin a single capsule having a fixed ratio of active ingredients or inmultiple, separate capsules for each active ingredient. In addition,such administration also encompasses use of each type of therapeuticagent in a sequential manner. In either case, the treatment regimen willprovide beneficial effects of the drug combination in treating theconditions or disorders described herein.

“JAK inhibitor” is used herein to refer to a compound that exhibits anIC₅₀ with respect to JAK1, JAK2, JAK3 and Tyk-2 activity of no more thanabout 100 μM and more typically not more than about 50 μM, as measuredin the JAK1, JAK2, JAK3 and Tyk-2 enzyme assays described generallyherein. In some embodiments, the compounds will exhibit an IC₅₀ withrespect JAK1, JAK2, JAK3 and Tyk-2 of about 1 μM to about 50 μM. IC₅₀ isthat concentration of inhibitor which reduces the activity of an enzyme(e.g., JAK1, JAK2, JAK3 and Tyk-2) to half-maximal level. Certaincompounds disclosed herein have been discovered to exhibit inhibitionagainst JAK1, JAK2, JAK3 and Tyk-2. In some embodiments, the compoundswill exhibit an IC₅₀ with respect to JAK1, JAK2, JAK3 and Tyk-2 of nomore than about 300 nM. In some embodiments, the compounds will exhibitan IC₅₀ with respect to JAK1, JAK2, JAK3 and Tyk-2 of no more than about1 nM. In certain embodiments, compounds will exhibit an IC₅₀ withrespect to JAK1, JAK2, JAK3 and Tyk-2 of no more than about 50 μM; infurther embodiments, compounds will exhibit an IC₅₀ with respect toJAK1, JAK2, JAK3 and Tyk-2 of no more than about 10 μM; in yet furtherembodiments, compounds will exhibit an IC₅₀ with respect to JAK1, JAK2,JAK3 and Tyk-2 of not more than about 5 μM; in yet further embodiments,compounds will exhibit an IC₅₀ with respect to JAK1, JAK2, JAK3 andTyk-2 of not more than about 1 μM, as measured in the JAK1, JAK2, JAK3and Tyk-2 assays described herein.

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder oron the effecting of a clinical endpoint.

As used herein, the term “therapeutic” or “therapeutic agent” or“pharmaceutically active agent” means an agent utilized to treat,combat, ameliorate, prevent or improve an unwanted condition or diseaseof a patient. In part, embodiments of the present invention are directedto the treatment of JAK-mediated diseases.

A “therapeutically effective amount” or “effective amount” of acomposition is a predetermined amount calculated to achieve the desiredeffect, i.e., to inhibit, block, or reverse the activation, migration,or proliferation of cells. The activity contemplated by the presentmethods includes both medical therapeutic and/or prophylactic treatment,as appropriate. The specific dose of a compound administered accordingto this invention to obtain therapeutic and/or prophylactic effectswill, of course, be determined by the particular circumstancessurrounding the case, including, for example, the compound administered,the route of administration, and the condition being treated. Thecompounds are effective over a wide dosage range and, for example,dosages per day will normally fall within the range of from 0.001 to 10mg/kg, more usually in the range of from 0.01 to 1 mg/kg. However, itwill be understood that the effective amount administered will bedetermined by the physician in the light of the relevant circumstancesincluding the condition to be treated, the choice of compound to beadministered, and the chosen route of administration, and therefore theabove dosage ranges are not intended to limit the scope of the inventionin any way. A therapeutically effective amount of compound of thisinvention is typically an amount such that when it is administered in aphysiologically tolerable excipient composition, it is sufficient toachieve an effective systemic concentration or local concentration inthe tissue.

The term “therapeutically acceptable” refers to those compounds, or aderivative thereof, which are suitable for use in contact with thetissues of patients without undue toxicity, irritation, and allergicresponse, are commensurate with a reasonable benefit/risk ratio, and areeffective for their intended use.

The terms “treat,” “treated,” “treating”, or “treatment” as used hereinrefers to both therapeutic treatment and prophylactic or preventativemeasures, wherein the object is to prevent or slow down (lessen) anundesired physiological condition, disorder or disease, or to obtainbeneficial or desired clinical results. For the purposes of thisinvention, beneficial or desired clinical results include, but are notlimited to, alleviation of symptoms; diminishment of the extent of thecondition, disorder or disease; stabilization (i.e., not worsening) ofthe state of the condition, disorder or disease; delay in onset orslowing of the progression of the condition, disorder or disease;amelioration of the condition, disorder or disease state; and remission(whether partial or total, whether induction of or maintenance of),whether detectable or undetectable, or enhancement or improvement of thecondition, disorder or disease. Treatment includes eliciting aclinically significant response without excessive levels of sideeffects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment. Treatment may also bepreemptive in nature, i.e., it may include prevention of disease.Prevention of a disease may involve complete protection from disease,for example as in the case of prevention of infection with a pathogen,or may involve prevention of disease progression. For example,prevention of a disease may not mean complete foreclosure of any effectrelated to the diseases at any level, but instead may mean prevention ofthe symptoms of a disease to a clinically significant or detectablelevel. Prevention of diseases may also mean prevention of progression ofa disease to a later stage of the disease and prolonging disease-freesurvival as compared to disease-free survival if not receiving treatmentand prolonging disease-free survival as compared to disease-freesurvival if not receiving treatment.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic directly into or onto a target tissue or toadminister a therapeutic to a patient whereby the therapeutic positivelyimpacts the tissue to which it is targeted. Thus, as used herein, theterm “administering”, when used in conjunction with a compound ofembodiments herein, can include, but is not limited to, providing thecompound into or onto the target tissue; providing the compoundsystemically to a patient by, e.g., intravenous injection whereby thetherapeutic reaches the target tissue; providing the compound in theform of the encoding sequence thereof to the target tissue (e.g., byso-called gene-therapy techniques). “Administering” a composition may beaccomplished by injection, topically, orally, or by any of these methodsin combination with other known techniques.

The term “patient” is generally synonymous with the term “subject” andincludes all mammals including humans. Examples of patients includehumans, livestock such as cows, goats, sheep, pigs, and rabbits, andcompanion animals such as dogs, cats, rabbits, and horses. Preferably,the patient is a human.

The terms “excipient” and “pharmaceutically acceptable excipient” asused herein are intended to be generally synonymous, and is usedinterchangeably with, the terms “carrier,” “pharmaceutically acceptablecarrier,” “diluent,” “pharmaceutically acceptable diluent.”

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds disclosed herein which arewater or oil-soluble or dispersible and therapeutically acceptable asdefined herein. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting the appropriatecompound in the form of the free base with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, succinate, sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds disclosed herein can be quaternized with methyl, ethyl,propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl,dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and sterylchlorides, bromides, and iodides; and benzyl and phenethyl bromides.Examples of acids which can be employed to form therapeuticallyacceptable addition salts include inorganic acids such as hydrochloric,hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic,maleic, succinic, and citric. Salts can also be formed by coordinationof the compounds with an alkali metal or alkaline earth ion. Hence, thepresent invention contemplates sodium, potassium, magnesium, and calciumsalts of the compounds disclosed herein, and the like.

Embodiments of the present invention are directed to compounds andpharmaceutical compositions comprising such compounds, which have beenfound to inhibit JAK kinase have been discovered, together with methodsof synthesizing and using the compounds including, without limitation,methods for the treatment of JAK mediated diseases in a patient byadministering the compounds. In some embodiments the compounds andpharmaceutical compositions are administered topically.

Compounds of the present invention may be selective amongst the JAKisoforms in various ways. For example, compounds described herein may beselective for JAK1, JAK2, JAK3, and/or Tyk-2 over other isoforms, haveequal potency against all isoforms, or be selective for only oneisoform. In certain embodiments, compounds of the present invention areselective for JAK1 over other isoforms. In some embodiments, thecompounds disclosed herein are selective for JAK1 over JAK2 and Tyk-2.Selectivity may be determined using enzyme assays, cellular assays orboth. In some embodiments, the compounds disclosed herein are at leastabout 10× more potent for JAK1 associated receptors compared to JAK2associate receptors. In some embodiments, the compounds disclosed hereinare at least about 10× selective for JAK1 associated receptors overTyk-2 associated receptors.

Compounds

Embodiments herein are directed to compounds and pharmaceuticalcompositions comprising such compounds, which have been found to inhibitJAK kinases, together with methods of synthesizing and using thecompounds. Some embodiments include methods for the treatment ofdiseases in a patient by administering the compounds of embodimentsherein.

Certain compounds disclosed herein may possess useful JAK inhibitingactivity and may be used in the treatment or prophylaxis of a disease orcondition in which JAK kinases play an active role. Thus, embodimentsare also directed to pharmaceutical compositions comprising one or morecompounds disclosed herein together with a pharmaceutically acceptablecarrier, as well as methods of making and using the compounds andcompositions. Certain embodiments are directed to methods for inhibitingJAK kinases. Other embodiments are directed to methods for treating aJAK-mediated disorder in a patient in need of such treatment, comprisingadministering to said patient a therapeutically effective amount of acompound or composition according to the present invention. Alsoprovided is the use of certain compounds disclosed herein in themanufacture of a medicament for the treatment of a disease or conditionameliorated by the inhibition of JAK kinase.

In some embodiments, the compounds disclosed herein have been designedto be poorly absorbed to minimize systemic exposure. In someembodiments, the compounds disclosed herein have been designed to berapidly metabolized to minimize systemic exposure. In some embodiments,the compounds disclosed herein are designed to exert their effect at thedesired site of action, for example in the gastrointestinal tract (e.g.,the colon), to decrease the risk of significant systemic effects oradverse systemic effects. In some embodiments, the compounds disclosedherein are gut-restricted compounds.

Also provided are embodiments wherein any embodiment herein may becombined with any one or more of the other embodiments, unless otherwisestated and provided the combination is not mutually exclusive.

Also provided is a compound chosen from the Examples disclosed herein.The compounds of embodiments herein may also refer to a derivativethereof, or a combination of the foregoing of the compounds ofembodiments herein.

Compounds described herein may contain one or more stereogenic centersand may thus exist as stereoisomers. Embodiments herein includes allsuch possible stereoisomers as substantially pure resolvedstereoisomers, racemic mixtures thereof, as well as mixtures ofdiastereomers. In some embodiments, the formulas are shown without adefinitive stereochemistry at certain positions. In other embodiments,the compounds are isolated as single stereoisomers, but the absoluteconfigurations of the stereogenic centers are unknown or only therelative stereochemical configuration (i.e., cis or trans isomerism) isknown. In such embodiments, the formulas are shown with provisionallyassigned absolute assignments to denote that they are singlestereoisomers and relative stereochemical configuration is likewisedescribed. Embodiments herein include all stereoisomers of such formulasand pharmaceutically acceptable salts thereof. Diastereoisomeric pairsof enantiomers may be separated by, for example, fractionalcrystallization from a suitable solvent, and the pair of enantiomersthus obtained may be separated into individual stereoisomers byconventional means, for example by the use of an optically active acidor base as a resolving agent or on a chiral HPLC column. Further, anystereoisomer of a compound of the general formula may be obtained bystereospecific or stereoselective synthesis using optically pure orenantioenriched starting materials or reagents of known configuration.The scope of embodiments herein as described and claimed encompasses theracemic forms of the compounds as well as the individual enantiomers,diastereomers, stereoisomers and stereoisomer-enriched mixtures.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable enantioenriched oroptically pure precursors or resolution of the racemate using, forexample, chiral high pressure liquid chromatography (HPLC).Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound contains an acidic or basic moiety, an acidor base such as tartaric acid or 1-phenylethylamine. The resultingdiastereomeric mixture may be separated by chromatography and/orfractional crystallization and one or both of the diastereoisomersconverted to the corresponding pure enantiomer(s) by means well known toone skilled in the art. Chiral compounds of embodiments herein (andchiral precursors thereof) may be obtained in enantiomerically-enrichedform using chromatography, typically HPLC, on an asymmetric resin with amobile phase consisting of a hydrocarbon, typically heptane or hexane,containing from 0 to 50% isopropanol, typically from 2 to 20%, and from0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration ofthe eluate affords the enriched mixture. Stereoisomer conglomerates maybe separated by conventional techniques known to those skilled in theart. See, e.g., “Stereochemistry of Organic Compounds” by Ernest L.Eliel (Wiley, New York, 1994).

Atropisomers are stereoisomers resulting from hindered rotation aboutsingle bonds where the steric strain barrier to rotation is high enoughto allow for the isolation of the conformers. Oki (Oki, M; Topics inStereochemistry 1983, 1) defined atropisomers as conformers thatinterconvert with a half-life of more than 1000 seconds at a giventemperature. The scope of embodiments herein as described and claimedencompasses the racemic forms of the compounds as well as the individualatropisomers (an atropisomer “substantially free” of its correspondingenantiomer) and stereoisomer-enriched mixtures, i.e. mixtures ofatropisomers.

Separation of atropisomers is possibly by chiral resolution methods suchas selective crystallization. In an atropo-enantioselective oratroposelective synthesis one atropisomer is formed at the expense ofthe other. Atroposelective synthesis may be carried out by use of chiralauxiliaries like a Corey-Bakshi-Shibata (CBS) catalyst (asymmetriccatalyst derived from proline) in the total synthesis of knipholone orby approaches based on thermodynamic equilibration when an isomerizationreaction favors one atropisomer over the other.

Suitable pharmaceutically acceptable acid addition salts of thecompounds of embodiments herein may be prepared from an inorganic acidor an organic acid. All of these salts may be prepared by conventionalmeans from the corresponding compound of embodiments herein by treating,for example, the compound with the appropriate acid or base.

Pharmaceutically acceptable acids include both inorganic acids, forexample hydrochloric, hydrobromic, hydroiodic, nitric, carbonic,sulfuric, phosphoric and diphosphoric acid; and organic acids, forexample formic, acetic, trifluoroacetic, propionic, succinic, glycolic,embonic (pamoic), methanesulfonic, ethanesulfonic,2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic,sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic,O-hydroxybutyric, malonic, galactic, galacturonic, citric, fumaric,gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic,oxalic, pantothenic, succinic, tartaric, benzoic, acetic, xinafoic(1-hydroxy-2-naphthoic acid), napadisilic (1,5-naphthalenedisulfonicacid) and the like.

Salts derived from pharmaceutically-acceptable inorganic bases includealuminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc and the like.Salts derived from pharmaceutically-acceptable organic bases includesalts of primary, secondary and tertiary amines, including alkyl amines,arylalkyl amines, heterocyclyl amines, cyclic amines,naturally-occurring amines and the like, such as arginine, betaine,caffeine, choline, chloroprocaine, diethanolamine, N-methylglucamine,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like.

Other preferred salts according to embodiments herein are quaternaryammonium compounds wherein an equivalent of an anion (X—) is associatedwith the positive charge of the N atom. X— may be an anion of variousmineral acids such as, for example, chloride, bromide, iodide, sulphate,nitrate, phosphate, or an anion of an organic acid such as, for example,acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate,malate, mandelate, trifluoroacetate, methanesulphonate andp-toluenesulphonate. X— is preferably an anion selected from chloride,bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinateor trifluoroacetate. More preferably X— is chloride, bromide,trifluoroacetate or methanesulphonate.

The compounds of embodiments herein may exist in both unsolvated andsolvated forms. The term solvate is used herein to describe a molecularcomplex comprising a compound of embodiments herein and an amount of oneor more pharmaceutically acceptable solvent molecules. The term hydrateis employed when said solvent is water. Examples of solvate formsinclude, but are not limited to, compounds of embodiments herein inassociation with water, acetone, dichloromethane, 2-propanol, ethanol,methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid,ethanolamine, or mixtures thereof. It is specifically contemplated thatin embodiments herein one solvent molecule can be associated with onemolecule of the compounds of embodiments herein, such as a hydrate.

Furthermore, it is specifically contemplated that in embodiments herein,more than one solvent molecule may be associated with one molecule ofthe compounds of embodiments herein, such as a dihydrate. Additionally,it is specifically contemplated that in embodiments herein less than onesolvent molecule may be associated with one molecule of the compounds ofembodiments herein, such as a hemihydrate. Furthermore, solvates ofembodiments herein are contemplated as solvates of compounds ofembodiments herein that retain the biological effectiveness of thenon-solvate form of the compounds.

Embodiments herein also include isotopically-labeled compounds ofembodiments herein, wherein one or more atoms is replaced by an atomhaving the same atomic number, but an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes suitable for inclusion in the compounds ofembodiments herein include isotopes of hydrogen, such as ²H and ³H,carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³¹Cl, fluorine, suchas ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N,oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulfur,such as ³⁵S. Certain isotopically-labeled compounds of embodimentsherein, for example, those incorporating a radioactive isotope, areuseful in drug and/or substrate tissue distribution studies. Theradioactive isotopes tritium, ³H, and carbon-14, ¹⁴C, are particularlyuseful for this purpose in view of their ease of incorporation and readymeans of detection. Substitution with heavier isotopes such asdeuterium, ²H, may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example, increased in vivo half-life orreduced dosage requirements, and hence may be preferred in somecircumstances. Substitution with positron emitting isotopes, such as¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography(PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds of embodiments herein can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

Preferred isotopically-labeled compounds include deuterated derivativesof the compounds of embodiments herein. As used herein, the termdeuterated derivative embraces compounds of embodiments herein where ina particular position at least one hydrogen atom is replaced bydeuterium. Deuterium (D or ²H) is a stable isotope of hydrogen which ispresent at a natural abundance of 0.015 molar %.

Hydrogen deuterium exchange (deuterium incorporation) is a chemicalreaction in which a covalently bonded hydrogen atom is replaced by adeuterium atom. Said exchange (incorporation) reaction can be total orpartial.

Typically, a deuterated derivative of a compound of embodiments hereinhas an isotopic enrichment factor (ratio between the isotopic abundanceand the natural abundance of that isotope, i.e. the percentage ofincorporation of deuterium at a given position in a molecule in theplace of hydrogen) for each deuterium present at a site designated as apotential site of deuteration on the compound of at least 3500 (52.5%deuterium incorporation).

In some embodiments, the isotopic enrichment factor is at least 5000(75% deuterium). In some embodiments, the isotopic enrichment factor isat least 6333.3 (95% deuterium incorporation). In some embodiments, theisotopic enrichment factor is at least 6633.3 (99.5% deuteriumincorporation). It is understood that the isotopic enrichment factor ofeach deuterium present at a site designated as a site of deuteration isindependent from the other deuteration sites.

The isotopic enrichment factor can be determined using conventionalanalytical methods known to one of ordinary skilled in the art,including mass spectrometry (MS) and nuclear magnetic resonance (NMR).

The term “prodrug” refers to a compound that is made more active invivo. Certain compounds disclosed herein may also exist as prodrugs, asdescribed in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compoundsdescribed herein are structurally modified forms of the compound thatreadily undergo chemical changes under physiological conditions toprovide the compound. Additionally, prodrugs can be converted to thecompound by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to a compound when placedin a transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the compound, or parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A wide variety of prodrug derivativesare known in the art, such as those that rely on hydrolytic cleavage oroxidative activation of the prodrug. An example, without limitation, ofa prodrug would be a compound which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound.

Prodrugs of the compounds described herein are also within the scope ofembodiments herein. Thus, certain derivatives of the compounds ofembodiments herein, which derivatives may have little or nopharmacological activity themselves, when administered into or onto thebody may be converted into compounds of embodiments herein having thedesired activity, for example, by hydrolytic cleavage. Such derivativesare referred to as ‘prodrugs’. Further information on the use ofprodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14,ACS Symposium Series (T. Higuchi and W. Stella) and BioreversibleCarriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, AmericanPharmaceutical Association).

Prodrugs in accordance with embodiments herein can, for example, beproduced by replacing appropriate functionalities present in thecompounds of embodiments herein with certain moieties known to thoseskilled in the art as ‘pro-moieties’ as described, for example, inDesign of Prodrugs by H. Bundgaard (Elsevier, 1985).

In the case of compounds of embodiments herein that are solids, it isunderstood by those skilled in the art that the inventive compounds andsalts may exist in different crystalline or polymorphic forms, or in anamorphous form, all of which are intended to be within the scope ofembodiments herein.

The compounds disclosed herein can exist as and therefore include allstereoisomers, tautomers, conformational isomers and mixtures thereof inall proportions as well as isotopic forms such as deuterated compounds.

The compounds disclosed herein can exist as therapeutically acceptablesalts. The present invention includes compounds listed above in the formof salts, including acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable. However, salts ofnon-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Basic additionsalts may also be formed and be pharmaceutically acceptable. For a morecomplete discussion of the preparation and selection of salts, refer toPharmaceutical Salts: Properties, Selection, and Use (Stahl, P.Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

In certain embodiments, compounds have structural Formula (I):

wherein:

-   -   R₁ is selected from CN or a heteroaryl group and is optionally        substituted at the one or more available nitrogen atoms with a        group independently selected from H or C₁-C₅alkyl and at one or        more available carbon atoms with substituents wherein each        substituent is independently selected from H, halogen, CN,        —C₁-C₄alkyl, —C₀-C₆alkylC₃-C₆cycloalkyl,        —(C₀-C₆alkyl)C₃-C₆heterocycle, —OH, —SO₂R₉, —SO₂R₉, —SR₉,        —NHSO₂R₉, —OSO₂R₉, —C₀-C₆alkylSO₂R₉, C₀-C₆alkylCOR₉,        C₀-C₆alkylNR₇C(O)NR₇R₈, C₀-C₆alkylOC(O)NR₇R₈,        C₀-C₆alkylNR₇SO₂R₉, —C₀-C₆alkylNR₇COR₉—OC₁-C₆alkyl,        —OC₀-C₆alkylC₃-C₆cycloalkyl, —OC₀-C₆alkylC₃-C₆heterocycle,        —OC₀-C₆alkylNR₇C(O)NR₇R₈, —OC₀-C₆alkylOC(O)NR₇R₈,        —OC₀-C₆alkylNR₇SO₂R₉, —OC₀-C₆alkylNR₇COR₉, —NR₇R₈,        —NR₇C₀-C₆alkylC₁-C₆alkyl, —NR₇C₀-C₆alkylC₃-C₆cycloalkyl,        —NR₇C₀-C₆alkylNR₇C(O)NR₇R₈, —NR₇C₀-C₆alkylOC(O)NR₇R₈,        —NR₇C₀-C₆alkylNR₇SO₂R₉, —NR₇C₀-C₆alkylNR₇COR₉,        —NR₇C₀-C₆alkylC₃-C₆heterocycle, aryl and heteroaryl wherein each        alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl group is        optionally substituted with one or more groups selected from:        halogen, —OH, —C₀-C₆alkylNR₇R₈, —C₀-C₆alkylOH, —SO₂R₉, —SOR₉,        —NHSO₂R₉, —C₀-C₆alkylNR₇R₄, CN, —C₁-C₅alkylalkoxy, C₁-C₅alkoxy        or —O—C₁-C₅alkyl;    -   R₂ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or        —C₁-C₂alkyl-C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl        groups are optionally substituted with one or more groups        selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0, 1 or 2;    -   Ring A is substituted at one or more carbons with one, two, or        three R₃ substituents wherein each R₃ substituent is        independently selected from H, halogen, —C₁-C₄alkyl,        —C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkyl wherein each alkyl or        cycloalkyl group is optionally substituted with one or more        groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy, or        —O—C₁-C₅alkyl;    -   Two R₃ groups on the same or different carbon atoms of the ring        A may be optionally joined to form a spirocyclic or bicyclic        ring system with ring A;    -   R₄ is selected from —C(O)—R₆, —CH₂R₆, —C(O)—C₁-C₅alkyl, or        —C(O)—C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl groups        may be optionally substituted with one or more groups selected        from —OH, halogen, alkyne, or —CN;    -   R₅ is selected from —C₁-C₅alkyl, or —C₃-C₆cycloalkyl wherein the        alkyl or cycloalkyl groups may be optionally substituted by one        or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl,        —C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇R₈, —O-aryl, —O-heteroaryl,        aryl, or heteroaryl wherein the alkyl, cycloalkyl, aryl or        heteroaryl groups can be optionally substituted by one or more        groups selected from halogen, —CN, alkyne, —OH, trifluoromethyl,        —O—C₁-C₅alkyl, or —O—C₃-C₆cycloalkyl;    -   R₇ and R₈ are independently selected from H, —C₁-C₅ alkyl,        —C₁-C₅ alkoxy, or —C₃-C₅ cycloalkyl wherein the alkyl groups may        be optionally substituted by one or more groups selected from        halogen, —OH, or —CN;    -   R₇ and R₈ may be optionally joined to form a ring to form a        heterocycle such as piperidine, pyrrolidine, or with another        heteroatom to form a ring such as morpholine wherein the        heterocyclic ring may be optionally substituted by one or more        groups selected from halogen, —OH, NH₂, NHMe, NMe₂, or —CN; and    -   R₉ is selected from H, —C₁-C₅alkyl, —OC₁-C₅alkyl,        —C₃-C₆cycloalkyl, and NR₇R₈ wherein the alkyl, heterocycle, or        cycloalkyl groups may be optionally substituted by one or more        groups selected from halogen, —OH, NH₂, NHMe, NMe₂, or —CN.

In certain embodiments, compounds have structural Formula (II):

wherein:

-   -   R₁₀ is selected from CN or a heteroaryl group and is optionally        substituted at the one or more available nitrogen atoms with a        group independently selected from H or C₁-C₅alkyl and at one or        more available carbon atoms with substituents wherein each        substituent is independently selected from H, halogen, CN,        —C₁-C₄alkyl, —C₀-C₆alkylC₃-C₆cycloalkyl,        —(C₀-C₆alkyl)C₃-C₆heterocycle, —OH, —SO₂R₉₀, —NHSO₂R₉₀,        —OSO₂R₉₀, —C₀-C₆alkylSO₂R₉₀, C₀-C₆alkylCOR₉₀,        C₀-C₆alkylNR₇₀C(O)NR₇₀R₈₀, C₀-C₆alkylOC(O)NR₇₀R₈₀,        C₀-C₆alkylNR₇₀SO₂R₉₀, —C₀-C₆alkylNR₇₀COR₉₀—OC₁-C₆alkyl,        —OC₀-C₆alkylC₃-C₆cycloalkyl, —OC₀-C₆alkylC₃-C₆heterocycle,        —OC₀-C₆alkylNR₇₀C(O)NR₇₀R₈₀, —OC₀-C₆alkylOC(O)NR₇₀R₈₀,        —OC₀-C₆alkylNR₇₀SO₂R₉₀, —OC₀-C₆alkylNR₇₀COR₉₀, —NR₇₀R₈₀,        —NR₇₀C₀-C₆alkylC₁-C₆alkyl, —NR₇₀C₀-C₆alkylC₃-C₆cycloalkyl,        —NR₇₀C₀-C₆alkylNR₇C(O)NR₇₀R₈₀, —NR₇₀C₀-C₆alkylOC(O)NR₇₀R₈₀,        —NR₇₀C₀-C₆alkylNR₇₀SO₂R₉₀, —NR₇₀C₀-C₆alkylNR₇₀COR₉₀,        —NR₇₀C₀-C₆alkylC₃-C₆heterocycle, aryl and heteroaryl wherein        each alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl group        is optionally substituted with one or more groups selected from:        halogen, —OH, —C₀-C₆alkylNR₇₀R₈₀, —C₀-C₆alkylOH, —SO₂R₉₀,        —SOR₉₀, —NHSO₂R₉₀, —C₀-C₆alkylNR₇₀R₄₀, CN, —C₁-C₅alkylalkoxy,        C₁-C₅alkoxy or —O—C₁-C₅alkyl;    -   R₂₀ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or        —C₁-C₂alkyl-C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl        groups are optionally substituted with one or more groups        selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0, 1 or 2;    -   Ring B is substituted at one or more carbons with one, two, or        three R₃₀ substituents wherein each R₃₀ substituent is        independently selected from H, halogen, —C₁-C₄alkyl,        —C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkyl wherein each alkyl or        cycloalkyl group is optionally substituted with one or more        groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy, or        —O—C₁-C₅alkyl;    -   Two R₃₀ groups on the same or different carbon atoms of the ring        B may be optionally joined to form a spirocyclic or bicyclic        ring system with ring B;    -   R₄₀ is selected from —C(O)—R₆₀, —CH₂R₆₀, —C(O)—C₁-C₅alkyl, or        —C(O)—C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl groups        may be optionally substituted with one or more groups selected        from —OH, halogen, alkyne, or —CN;    -   R₅₀ is selected from —C₁-C₅alkyl, or —C₃-C₆cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₀ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl,        —C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇₀R₈₀, —O-aryl, —O-heteroaryl,        aryl, or heteroaryl wherein the alkyl, cycloalkyl, aryl or        heteroaryl groups can be optionally substituted by one or more        groups selected from halogen, —CN, alkyne, —OH, trifluoromethyl,        —O—C₁-C₅alkyl, or —O—C₃-C₆cycloalkyl;    -   R₇₀ and R₈₀ are independently selected from H, —C₁-C₅ alkyl,        —C₁-C₅ alkoxy, or —C₃-C₅ cycloalkyl wherein the alkyl groups may        be optionally substituted by one or more groups selected from        halogen, —OH, or —CN;    -   R₇₀ and R₈₀ may be optionally joined to form a ring to form a        heterocycle such as piperidine, pyrrolidine, or with another        heteroatom to form a ring such as morpholine wherein the        heterocyclic ring may be optionally substituted by one or more        groups selected from halogen, —OH, NH₂, NHMe, NMe₂, or —CN; and    -   R₉₀ is selected from H, —C₁-C₅alkyl, —C₃-C₆cycloalkyl, and        NR₇₀R₈₀ wherein the alkyl, heterocycle, or cycloalkyl groups may        be optionally substituted by one or more groups selected from        halogen, —OH, NH₂, NHMe, NMe₂, or —CN.

In certain embodiments, compounds have structural Formula (III):

wherein:

-   -   R₁₀₀ is selected from CN or a heteroaryl group and is        substituted at the one or more available nitrogen atoms with a        group independently selected from H or C₁-C₅alkyl and at one or        more available carbon atoms with substituents wherein each        substituent is independently selected from H, halogen, CN,        —C₁-C₄alkyl, —C₃-C₆cycloalkyl, —OH, —O—C₁-C₅alkyl, —SO₂R₉₀₀,        —NHSO₂R₉₀₀, —OSO₂R₉₀₀, —CH₂SO₂R₉₀₀, (CH₂)_(n)COR₉₀₀, aryl and        heteroaryl wherein each alkyl, cycloalkyl, aryl or heteroaryl        group is optionally substituted with one or more groups selected        from: halogen, —OH, NH₂, NH—C₁-C₅alkyl, CN, —C₁-C₅alkylalkoxy,        C₁-C₅alkoxy or —O—C₁-C₅alkyl;    -   R₂₀₀ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or        —C₁-C₂alkyl-C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl        groups are optionally substituted with one or more groups        selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0, 1 or 2;    -   Ring C is substituted at one or more carbons with one, two, or        three R₃₀₀ substituents wherein each R₃₀₀ substituent is        independently selected from H, halogen, —C₁-C₄alkyl,        —C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkyl wherein each alkyl or        cycloalkyl group is optionally substituted with one or more        groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy, or        —O—C₁-C₅alkyl;    -   Two R₃₀₀ groups on the same or different carbon atoms of the        ring C may be optionally joined to form a spirocyclic or        bicyclic ring system with ring C;    -   R₄₀₀ is selected from —C(O)—R₆₀₀, —CH₂R₆₀₀, —C(O)—C₁-C₅alkyl, or        —C(O)—C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl groups        may be optionally substituted with one or more groups selected        from —OH, halogen, alkyne, or —CN;    -   R₅₀₀ is selected from —C₁-C₅alkyl, or —C₃-C₆cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₀₀ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl,        —C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇₀₀R₈₀₀, —O-aryl, —O-heteroaryl,        aryl, or heteroaryl wherein the alkyl, cycloalkyl, aryl or        heteroaryl groups can be optionally substituted by one or more        groups selected from halogen, —CN, alkyne, —OH, trifluoromethyl,        —O—C₁-C₅alkyl, or —O—C₃-C₆cycloalkyl;    -   R₇₀₀ and R₈₀₀ are independently selected from H, —C₁-C₅ alkyl,        —C₁-C₅ alkoxy, or —C₃-C₅ cycloalkyl wherein the alkyl groups may        be optionally substituted by one or more groups selected from        halogen, —OH, or —CN;    -   R₇₀₀ and R₈₀₀ may be optionally joined to form a ring to form a        heterocycle such as piperidine, pyrrolidine, or with another        heteroatom to form a ring such as morpholine; and R₉₀₀ is        selected from H, —C₁-C₅alkyl, —C₃-C₆cycloalkyl, and NR₇₀₀R₈₀₀        wherein the alkyl groups may be optionally substituted by one or        more groups selected from halogen, —OH, or —CN.

In certain embodiments, compounds have structural Formula (IV):

wherein:

-   -   R₁₀₀₀ is selected from CN or a heteroaryl group and is        substituted at the one or more available nitrogen atoms with a        group independently selected from H or C₁-C₅alkyl and at one or        more available carbon atoms with substituents wherein each        substituent is independently selected from H, halogen, CN,        —C₁-C₄alkyl, —C₃-C₆cycloalkyl, —OH, —O—C₁-C₅alkyl, —SO₂R₉₀₀₀,        —NHSO₂R₉₀₀₀, —OSO₂R₉₀₀₀, —CH₂SO₂R₉₀₀₀, (CH₂)_(n)COR₉₀₀₀, aryl        and heteroaryl wherein each alkyl, cycloalkyl, aryl or        heteroaryl group is optionally substituted with one or more        groups selected from: halogen, —OH, NH₂, NH—C₁-C₅alkyl, CN,        —C₁-C₅alkylalkoxy, C₁-C₅alkoxy or —O—C₁-C₅alkyl;    -   R₂₀₀₀ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or        —C₁-C₂alkyl-C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl        groups are optionally substituted with one or more groups        selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   n is 0, 1 or 2;    -   Ring D is substituted at one or more carbons with one, two, or        three R₃₀₀₀ substituents wherein each R₃₀₀₀ substituent is        independently selected from H, halogen, —C₁-C₄alkyl,        —C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkyl wherein each alkyl or        cycloalkyl group is optionally substituted with one or more        groups selected from: halogen, —OH, —C₁-C₅alkylalkoxy, or        —O—C₁-C₅alkyl;    -   Two R₃₀₀₀ groups on the same or different carbon atoms of the        ring D may be optionally joined to form a spirocyclic or        bicyclic ring system with ring D;    -   R₄₀₀₀ is selected from —C(O)—R₆₀₀₀, —CH₂R₆₀₀₀, —C(O)—C₁-C₅alkyl,        or —C(O)—C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl groups        may be optionally substituted with one or more groups selected        from —OH, halogen, alkyne, or —CN;    -   R₅₀₀₀ is selected from —C₁-C₅alkyl, or —C₃-C₆cycloalkyl wherein        the alkyl or cycloalkyl groups may be optionally substituted by        one or more groups selected from halogen, —OH, or —O—C₁-C₅alkyl;    -   R₆₀₀₀ is selected from —C₁-C₅alkyl, —C₃-C₆cycloalkyl,        —C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇₀₀₀R₈₀₀₀, —O-aryl,        —O-heteroaryl, aryl, or heteroaryl wherein the alkyl,        cycloalkyl, aryl or heteroaryl groups can be optionally        substituted by one or more groups selected from halogen, —CN,        alkyne, —OH, trifluoromethyl, —O—C₁-C₅alkyl, or        —O—C₃-C₆cycloalkyl;    -   R₇₀₀₀ and R₈₀₀₀ are independently selected from H, —C₁-C₅ alkyl,        —C₁-C₅ alkoxy, or —C₃-C₅ cycloalkyl wherein the alkyl groups may        be optionally substituted by one or more groups selected from        halogen, —OH, or —CN;    -   R₇₀₀₀ and R₈₀₀₀ may be optionally joined to form a ring to form        a heterocycle such as piperidine, pyrrolidine, or with another        heteroatom to form a ring such as morpholine; and    -   R₉₀₀₀ is selected from H, —C₁-C₅alkyl, —C₃-C₆cycloalkyl, and        NR₇₀₀₀R₈₀₀₀ wherein the alkyl groups may be optionally        substituted by one or more groups selected from halogen, —OH, or        —CN.

The invention is further illustrated by the following examples ofcompounds of Formula (I)

Example # Structure Name 1

(R)-3-oxo-3-(3-((5-(thiazol-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile 2

(R)-3-(3-((5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3-oxopropanenitrile 3

(R)-3-(3-((5-(2-methylthiazol-5-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 4

(R)-3-oxo-3-(3-((5-(thiazol-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile 5

(R)-3-(3-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 6

(R)-3-(3-((5-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3-oxopropanenitrile 7

(R)-3-(3-((5-(1,3,4-oxadiazol-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 8

rac-(R)-3-(3-((5-(1,3,4-thiadiazol-2-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 9

3-((3R,5S)-3-methyl-5-((5-(oxazol-2-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 10

3-((3S,5R)-3-methyl-5-((5-(oxazol-2-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 11

(R)-3-(3-((5-(4H-1,2,4-triazol-3-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 14

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5- yl)oxazole-4-carboxamide 15

(R)-3-(3-((5-(4-methylpyridin-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 16

(R)-3-oxo-3-(3-((5-(thiazol-5-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile 17

(R)-3-(3-((5-(1-methyl-1H-imidazol-2-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 18

(R)-3-(3-((5-(1H-pyrazol-5-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 19

(R)-3-(3-((5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3-oxopropanenitrile 20

(R)-3-(3-((5-(6-methylpyridin-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 21

(R)-3-oxo-3-(3-((5-(pyridin-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile 22

(R)-3-(3-((5-(5-methylpyridin-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 23

(R)-3-oxo-3-(3-((5-(pyrimidin-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile 24

(R)-3-oxo-3-(3-((5-(pyrimidin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile 25

(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5- carbonitrile 26

(R)-3-(3-((5-(3-methyl-1H-pyrazol-5-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 27

(R)-3-(3-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1- yl)propanenitrile 28

3-((2S,5R)-2-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) piperidin-1-yl)-3-oxopropanenitrile30

2-(4-(((3R,65)-1-(2-cyanoacetyl)-6- methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N- methyloxazole-4-carboxamide 31

2-(4-(((3R,5S)-1-(2-cyanoacetyl)-5- methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N- methyloxazole-4-carboxamide 32

2-(4-(((3S,5R)-1-(2-cyanoacetyl)-5- methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N- methyloxazole-4-carboxamide 33

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)- N-methyloxazole-4-carboxamide34

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethyl-oxazole-4-carboxamide 35

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)- N-methylthiazole-4-carboxamide36

(R)-3-(3-((5-(5-methyloxazol-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 37

(R)-3-(3-((5-(5-methyloxazol-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile 38

(R)-3-(3-((5-(1,2,4-oxadiazol-3-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 39

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)- N-methyloxazole-5-carboxamide40

3-((3R,5S)-3-((5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3- oxopropanenitrile 41

(R)-3-(3-((5-(isothiazol-3-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 42

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5- yl)thiazole-5-carboxylate 43

(R)-3-(3-((5-(2-methoxypyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) piperidin-1-yl)-3-oxopropanenitrile44

(R)-3-(3-((5-(6-aminopyridin-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 45

3-((3R)-3-((5-(5-(methylsulfinyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3-oxopropanenitrile 46

(R)-3-(3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile 47

(R)-3-(3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)propanenitrile48

(R)-3-(3-((5-(5-(methylsulfonyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile 49

(R)-3-(3-((5-(2-(methylthio)pyrimidin-4- yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 50

2-cyano-N-(1-(4-(4-(((R)-1-(2- cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)pyrrolidin-3-yl)-N-methylacetamide 51

(R)-3-(3-((5-(2-aminopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) piperidin-1-yl)-3-oxopropanenitrile 52

3-((3S,5R)-3-methyl-5-((5-(2- methylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 53

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)- N-methylthiazole-5-carboxamide54

(R)-N-(2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5- yl)pyridin-4-yl)N,N-dimethylsulfuric diamide 55

(R)-3-(3-((5-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile 56

(R)-N-(2-(4-((1-(2-cyanoacetyl)piperidin- 3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5- yl)pyridin-4-yl)methanesulfonamide 57

3-((3R,5S)-3-methyl-5-((5-(pyrimidin-4- yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 58

(R)-3-(3-((5-(1H-pyrazol-5-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 59

(R)-3-(3-((5-(3-(methylsulfonyl)phenyl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 60

(R)-3-(3-((5-(4-methylpyridin-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 61

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)- N-methylisonicotinamide 62

(R)-3-(3-((5-(1-(2-hydroxyethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3-oxopropanenitrile 63

(R)-3-(3-((5-(3-(hydroxymethyl)phenyl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 64

3-((3R,5S)-3-((5-(6- (hydroxymethyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 65

3-((3S,5R)-3-methyl-5-((5-(5- (methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3- oxopropanenitrile66

(R)-3-(3-((5-(5-acetyloxazol-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 67

N-((3R,5S)-1-((2,2- difluorocyclopropyl)methyl)-5-methylpiperidin-3-yl)-5-(thiazol-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine68

3-((3R,5S)-3-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 69

3-((3S,5R)-3-methyl-5-((5-(5- methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 70

3-((3R,5S)-3-((5-(5- (hydroxymethyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 71

3-((3R,5S)-3-((5-(5-(2-hydroxypropan-2-yl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3- oxopropanenitrile 72

3-((3R,5S)-3-((5-(5-(fluoromethyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 73

3-((3R,5S)-3-((5-(5-acetyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 74

3-((3R,5S)-3-((5-(4-acetyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 75

3-((3S,5R)-3-methyl-5-((5-(5- (methylsulfonyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3- oxopropanenitrile76

3-((3S,5R)-3-methyl-5-((5-(4- methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 77

(R)-3-(3-((5-(4-(methylsulfonyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3-oxopropanenitrile 78

3-((3S,5R)-3-methyl-5-((5-(4- (methylsulfonyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3- oxopropanenitrile79

3-((3S,5R)-3-methyl-5-((5-(5- methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1- yl)propanenitrile 80

3-((3S,5R)-3-methyl-5-((5-(4- methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1- yl)propanenitrile 81

3-((3R,5S)-3-((5-(4,5- bis(hydroxymethyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 82

3-((3R,5S)-3-((5-(5-(hydroxymethyl)-4- (methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 83

3-(4-(((1R,5R)-3-(2-cyanoacetyl)-5-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylisoxazole-5- carboxamide 84

3-((3R,5S)-3-((5-(5- (hydroxymethyl)isoxazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 85

3-((3R,5S)-3-((5-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 86

3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 87

3-((3R,5S)-3-((5-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin- 1-yl)-3-oxopropanenitrile 88

3-((3R,5S)-3-((5-(5-(2-hydroxypropan-2-yl)-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin- 1-yl)-3-oxopropanenitrile 89

3-((3R,5S)-3-((5-(5-(fluoromethyl)-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3- oxopropanenitrile 90

3-((3S,5R)-3-methyl-5-((5-(5- (methylsulfonyl)-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3-oxopropanenitrile 91

3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile 92

3-((3R,5S)-3-((5-(5-acetyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3- oxopropanenitrile 93

3-((3S,5R)-3-methyl-5-((5-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 94

3-((3S,5R)-3-methyl-5-((5-(thiazol-2-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 95

3-((3S,5R)-3-methyl-5-((5-(5- methylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 96

3-((3R,5S)-3-((5-(5- (hydroxymethyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 97

3-((3R,5S)-3-((5-(5-(2-hydroxypropan-2-yl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3- oxopropanenitrile 98

3-((3R,5S)-3-((5-(5-(fluoromethyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 99

3-((3R,5S)-3-((5-(5-acetylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 100

3-((3S,5R)-3-methyl-5-((5-(4- methylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 101

3-((3S,5R)-3-methyl-5-((5-(5- methylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1- yl)propanenitrile 102

3-((3S,5R)-3-methyl-5-((5-(4- methylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1- yl)propanenitrile 103

3-((3S,5R)-3-methyl-5-((5-(5- (methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)propanenitrile 104

(R)-3-(3-((5-(5-acetylthiazol-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 105

3-((3R,4R)-4-methyl-3-((5-(5- (methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3- oxopropanenitrile106

3-((3S,5R)-3-methyl-5-((5-(5- (methylsulfonyl)isothiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3- oxopropanenitrile107

3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 108

3-((3R,5S)-3-((5-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin- 1-yl)-3-oxopropanenitrile 109

3-((3R,5S)-3-((5-(5-(2-hydroxypropan-2-yl)-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin- 1-yl)-3-oxopropanenitrile 110

3-((3R,5S)-3-((5-(5-(fluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3- oxopropanenitrile 111

3-((3R,5S)-3-((5-(5-acetyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3- oxopropanenitrile 112

3-((3S,5R)-3-methyl-5-((5-(5- (methylsulfonyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3-oxopropanenitrile 113

3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile 114

3-((2S,5R)-2-methyl-5-((5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 115

3-((2S,5R)-5-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-2-methylpiperidin-1-yl)-3-oxopropanenitrile 116

3-((3R,4R)-4-methyl-3-((5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 117

3-((3R,4R)-3-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile 118

3-((3R,5S)-3-((5-(5-(1-fluorocyclopropyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin- 1-yl)-3-oxopropanenitrile 119

N-((3R,5S)-5-methyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine 120

3-((3S,5R)-3-methyl-5-((5-(3-methyl-1,2,4-thiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 121

3-((3R,5S)-3-((5-(6-acetylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 122

3-((3S,5R)-3-methyl-5-((5-(5- (methylsulfonyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3- oxopropanenitrile123

3-((3S,5R)-3-methyl-5-((5-(4- (methylsulfonyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3- oxopropanenitrile124

3-((3R,5S)-3-((5-(4-acetylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 125

3-((3S,5R)-3-methyl-5-((5-(6- methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 126

3-((3S,5R)-3-methyl-5-((5-(4- methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 127

3-((3R,5S)-3-((5-(4- (hydroxymethyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 128

3-((3S,5R)-3-methyl-5-((5-(pyrimidin-4- yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 129

3-((3R,5S)-3-((5-(2- (hydroxymethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 130

3-((3R,5S)-3-((5-(2- (fluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 131

3-((3R,5S)-3-((5-(2-methoxypyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)- 5-methylpiperidin-1-yl)-3-oxopropanenitrile 132

3-((3R,5S)-3-((5-(2-acetylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile 133

(R)-3-(3-((5-(4- (methylsulfonyl)pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3- oxopropanenitrile134

3-((3S,5R)-3-methyl-5-((5-(4- (methylsulfonyl)pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-3- oxopropanenitrile135

3-((3S,5R)-3-methyl-5-((5-(6- methylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3- oxopropanenitrile 136

3-((3R,5S)-3-((5-(6- (hydroxymethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile

The invention is further illustrated by the following examples ofcompounds of Formula (II)

Example # Structure Name 12

(1S,3R)-3-((5-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-ol 13

(1S,3R)-3-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-ol 29

2-(4-(((1S,3R)-3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide

In some embodiments, the compounds disclosed herein are gut-restrictedcompounds.

Pharmaceutical Compositions

Some embodiments herein are directed to a pharmaceutical compositioncomprising a compound of embodiments herein and a pharmaceuticallyacceptable excipient.

Also provided is a pharmaceutical composition comprising a compound asdisclosed herein, together with a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical compositions disclosed hereinare gut-restricted compounds.

While it may be possible for the compounds described herein to beadministered as the raw chemical, it is also possible to present them asa pharmaceutical composition. Accordingly, provided herein arepharmaceutical compositions which comprise one or more of certaincompounds disclosed herein, or a derivative thereof, together with oneor more pharmaceutically acceptable excipients thereof and optionallyone or more other therapeutic ingredients. The excipient(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Properformulation of the pharmaceutical composition is dependent upon theroute of administration chosen. Any of the well-known techniques andexcipients may be used as suitable and as understood in the art. Thepharmaceutical compositions disclosed herein may be manufactured in anymanner known in the art, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or compression processes.

In some embodiments, the pharmaceutical compositions for use inaccordance with embodiments herein can be formulated in conventionalmanner using one or more physiologically acceptable excipients.

The compositions include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, intrathecal, intradural,transmucosal, transdermal, rectal, intranasal, topical (including, forexample, dermal, buccal, sublingual and intraocular), intravitreal, orintravaginal administration although the most suitable route may dependupon for example the condition and disorder of the recipient. Thecomposition could include those suitable for administration by depotinjections or by implants. The composition could include those suitablefor administration by inhalation, such as, for example, a gas, vapor, orpowder. The composition could include those suitable for administration,e.g., as an aerosol via a nebulizer, humidifier, inhaler and vaporizeror the like. The compositions may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. Typically, these methods include the step of bringinginto association a compound disclosed herein or a derivative thereof(“active ingredient”) with the carrier which constitutes one or moreaccessory ingredients. In general, the compositions are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both and then,if necessary, shaping the product into the desired composition.

Compositions of the compounds disclosed herein suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All compositionsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Compositionsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The pharmaceuticalcompositions may take such forms as suspensions, solutions or emulsionsin oily or aqueous vehicles, and may contain formulatory agents such assuspending, stabilizing and/or dispersing agents. The compositions maybe presented in unit-dose or multi-dose containers, for example sealedampoules and vials, and may be stored in powder form or in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example, saline or sterile pyrogen-freewater, immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Pharmaceutical compositions for parenteral administration includeaqueous and non-aqueous (oily) sterile injection solutions of the activecompounds which may contain antioxidants, buffers, bacteriostats andsolutes which render the composition isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers or agents which increase the solubility ofthe compounds to allow for the preparation of highly concentratedsolutions.

In addition to the pharmaceutical compositions described previously, thecompounds may also be formulated as a depot preparation. Such longacting compositions may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

For buccal or sublingual administration, the pharmaceutical compositionsmay take the form of tablets, lozenges, pastilles, or gels formulated inconventional manner. Such compositions may comprise the activeingredient in a flavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds disclosed herein may be administered topically, thatis by non-systemic administration. This includes the application of acompound disclosed herein externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose. In contrast, systemic administration refers to oral, intravenous,intraperitoneal and intramuscular administration.

In some embodiments, the compounds disclosed herein may be administeredophthalmically. In some embodiments, the compounds disclosed herein maybe administered as an ophthalmic composition. The compounds ofembodiments herein may be administered as, for example, liquidpreparations, including eye lotions, spray, or eye drops for topicaladministration. In some embodiments, the compounds disclosed herein maybe administered as semi-solid preparations, for example, applied to theeyelid, such as cream, lotion, gel, ointment, or paste. In someembodiments, the compounds disclosed herein may be administered as soliddosage forms, for example, applied to the eye surface to producemodified release, such as a powder. In some embodiments, the compoundsof embodiments herein are administered through devices for surgicalimplantation, parenteral products, (e.g., intracorneal or intravitreousproducts), liquids for irrigation, or the like. In some embodiments, thepharmaceutical composition comprising the compounds disclosed herein aresterile and free from particulate matters. In some embodiments, thecompounds disclosed herein may be administered by intraocular injection,intraorbital injection, or an intravitreal injection. In someembodiments, the intraocular injection may be to the anterior chamber ofthe eye, posterior chamber of the eye, or a combination thereof. Forexample, the compounds disclosed herein may be administered to theposterior intraorbital region of the eye.

In some embodiments, pharmaceutical compositions suitable for topicaladministration include liquid or semi-liquid preparations suitable forpenetration through the skin to the site of inflammation such as asolution, powder, fluid emulsion, fluid suspension, semi-solid,ointment, paste, cream, gel, jelly, foam, liniment, lotion, and dropssuitable for administration to the eye, ear or nose. The activeingredient for topical administration may comprise, for example, from0.001% to 10% w/w (by weight) of the composition. In certainembodiments, the active ingredient may comprise as much as 10% w/w. Inother embodiments, it may comprise less than 5% w/w. In certainembodiments, the active ingredient may comprise from 2% w/w to 5% w/w.In other embodiments, it may comprise from 0.1% to 1% w/w of thecomposition.

Gels for topical or transdermal administration may comprise, generally,a mixture of volatile solvents, nonvolatile solvents, and water. Incertain embodiments, the volatile solvent component of the bufferedsolvent system may include lower (C₁-C₆) alkyl alcohols, lower alkylglycols and lower glycol polymers. In further embodiments, the volatilesolvent is ethanol. The volatile solvent component is thought to act asa penetration enhancer, while also producing a cooling effect on theskin as it evaporates. The nonvolatile solvent portion of the bufferedsolvent system is selected from lower alkylene glycols and lower glycolpolymers. In certain embodiments, propylene glycol is used. Thenonvolatile solvent slows the evaporation of the volatile solvent andreduces the vapor pressure of the buffered solvent system. The amount ofthis nonvolatile solvent component, as with the volatile solvent, isdetermined by the pharmaceutical compound or drug being used. When toolittle of the nonvolatile solvent is in the system, the pharmaceuticalcompound may crystallize due to evaporation of volatile solvent, whilean excess may result in a lack of bioavailability due to poor release ofdrug from solvent mixture. The buffer component of the buffered solventsystem may be selected from any buffer commonly used in the art; incertain embodiments, water is used. A common ratio of ingredients isabout 20% of the nonvolatile solvent, about 40% of the volatile solvent,and about 40% water. There are several optional ingredients which can beadded to the topical composition. These include, but are not limited to,chelators and gelling agents. Appropriate gelling agents can include,but are not limited to, semisynthetic cellulose derivatives (such ashydroxypropylmethylcellulose) and synthetic polymers, and cosmeticagents.

Lotions include those suitable for application to the skin or eye. Aneye lotion may comprise a sterile aqueous solution optionally containinga bactericide and may be prepared by methods similar to those for thepreparation of drops. Lotions or liniments for application to the skinmay also include an agent to hasten drying and to cool the skin, such asan alcohol or acetone, and/or a moisturizer such as glycerol or an oilsuch as castor oil or arachis oil.

Creams, ointments or pastes are semi-solid pharmaceutical compositionsof the active ingredient for external application. They may be made bymixing the active ingredient in finely-divided or powdered form, aloneor in solution or suspension in an aqueous or non-aqueous fluid, withthe aid of suitable machinery, with a greasy or non-greasy base. Thebase may comprise hydrocarbons such as hard, soft or liquid paraffin,glycerol, beeswax, a metallic soap; a mucilage; an oil of natural originsuch as almond, corn, arachis, castor or olive oil; wool fat or itsderivatives or a fatty acid such as steric or oleic acid together withan alcohol such as propylene glycol or a macrogel. The pharmaceuticalcomposition may incorporate any suitable surface active agent such as ananionic, cationic or non-ionic surfactant such as a sorbitan ester or apolyoxyethylene derivative thereof. Suspending agents such as naturalgums, cellulose derivatives or inorganic materials such as silicaceoussilicas, and other ingredients such as lanolin, may also be included.

Drops may comprise sterile aqueous or oily solutions or suspensions andmay be prepared by dissolving the active ingredient in a suitableaqueous solution of a bactericidal and/or fungicidal agent and/or anyother suitable preservative, and, in certain embodiments, including asurface active agent. The resulting solution may then be clarified byfiltration, transferred to a suitable container which is then sealed andsterilized by autoclaving or maintaining at 98-100° C. for half an hour.Alternatively, the solution may be sterilized by filtration andtransferred to the container by an aseptic technique. Examples ofbactericidal and fungicidal agents suitable for inclusion in the dropsare phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride(0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for thepreparation of an oily solution include glycerol, diluted alcohol andpropylene glycol.

Pharmaceutical compositions for topical administration in the mouth, forexample buccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia.

For administration by inhalation, compounds may be convenientlydelivered from an insufflator, nebulizer pressurized packs or otherconvenient means of delivering an aerosol spray. Pressurized packs maycomprise a suitable propellant such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form, in for example, capsules, cartridges,gelatin or blister packs from which the powder may be administered withthe aid of an inhalator or insufflator.

Preferred unit dosage pharmaceutical compositions are those containingan effective dose, as herein below recited, or an appropriate fractionthereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the pharmaceutical compositions described above mayinclude other agents conventional in the art having regard to the typeof pharmaceutical composition in question, for example those suitablefor oral administration may include flavoring agents.

Compounds may be administered at a dose of from 0.1 to 500 mg/kg perday. The dose range for adult humans is generally from 5 mg to 2 g/day.Tablets or other forms of presentation provided in discrete units mayconveniently contain an amount of one or more compounds which iseffective at such dosage or as a multiple of the same, for instance,units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

When employed as pharmaceuticals, the compounds can be administered inthe form of pharmaceutical compositions. These compositions can beprepared in a manner well known in the pharmaceutical arts, and can beadministered by a variety of routes, depending upon whether local orsystemic treatment is desired and upon the area to be treated.Administration of the disclosed compounds or compositions may be oral,parenteral (including subcutaneous, intradermal, intramuscular,intravenous, intraarticular, and intramedullary), pulmonary (e.g., byinhalation or insufflation of powders or aerosols, including bynebulizer; intratracheal or intranasal), intraperitoneal, intrathecal,intradural, transmucosal, transdermal, rectal, topical (includingdermal, buccal, sublingual and intraocular), or intravaginaladministration. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal, intramuscular or injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions for topical administration may includefoams, transdermal patches, ointments, lotions, creams, gels, solutions,fluid emulsions, fluid suspensions, semi-solids, pastes, drops,suppositories, sprays, liquids and powders. Conventional pharmaceuticalcarriers, aqueous, powder or oily bases, thickeners and the like may benecessary or desirable. Coated condoms, gloves and the like may also beuseful. In some embodiments, the compounds can be contained in suchpharmaceutical compositions with pharmaceutically acceptable diluents,fillers, disintegrants, binders, lubricants, surfactants, hydrophobicvehicles, water soluble vehicles, emulsifiers, buffers, humectants,moisturizers, solubilizers, preservatives and the like. The artisan canrefer to various pharmacologic references for guidance. For example,Modern Pharmaceutics, 5th Edition, Banker & Rhodes, CRC Press (2009);and Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, 13thEdition, McGraw Hill, N.Y. (2018) can be consulted.

In some embodiments, a method of treating a JAK kinase-mediated diseaseby administering a pharmaceutical composition of embodiments disclosedherein. In some embodiments, the compound is in a therapeuticallyeffective amount. In some embodiments, the therapeutically effectiveamount is an amount disclosed herein.

Some embodiments disclosed herein also include pharmaceuticalcompositions which contain, as the active ingredient, one or more of thecompounds disclosed herein in combination with one or morepharmaceutically acceptable carriers (excipients).

In some embodiments, a method of making a pharmaceutical compositioncomprises mixing the active ingredient with an excipient, diluting theactive ingredient using an excipient, or enclosing the active ingredientwithin a carrier in the form of, for example, a capsule, sachet, paper,or other container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the pharmaceuticalcompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose,including eutectic solvents, eutectic-based ionic liquids, or ionicliquids. The pharmaceutical compositions can additionally include:lubricating agents such as talc, magnesium stearate, and mineral oil;wetting agents; emulsifying and suspending agents; preserving agentssuch as methyl- and propylhydroxy-benzoates; sweetening agents; andflavoring agents. The pharmaceutical compositions can be formulated soas to provide quick, sustained or delayed release of the activeingredient after administration to the patient by employing proceduresknown in the art.

The pharmaceutical compositions can be formulated in a unit dosage form.The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and can begenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

In some embodiments, the pharmaceutical composition may comprise about0.01% to about 50% of one or more compounds disclosed herein. In someembodiments, the one or more compounds is in an amount of about 0.01% toabout 50%, about 0.01% to about 45%, about 0.01% to about 40%, about0.01% to about 30%, about 0.01% to about 20%, about 0.01% to about 10%,about 0.01% to about 5%, about 0.05% to about 50%, about 0.05% to about45%, about 0.05% to about 40%, about 0.05% to about 30%, about 0.05% toabout 20%, about 0.05% to about 10%, about 0.1% to about 50%, about 0.1%to about 45%, about 0.1% to about 40%, about 0.1% to about 30%, about0.1% to about 20%, about 0.1% to about 10%, about 0.1% to about 5%,about 0.5% to about 50%, about 0.5% to about 45%, about 0.5% to about40%, about 0.5% to about 30%, about 0.5% to about 20%, about 0.5% toabout 10%, about 0.5% to about 5%, about 1% to about 50%, about 1% toabout 45%, about 1% to about 40%, about 1% to about 35%, about 1% toabout 30%, about 1% to about 25%, about 1% to about 20%, about 1% toabout 15%, about 1% to about 10%, about 1% to about 5%, about 5% toabout 45%, about 5% to about 40%, about 5% to about 35%, about 5% toabout 30%, about 5% to about 25%, about 5% to about 20%, about 5% toabout 15%, about 5% to about 10%, about 10% to about 45%, about 10% toabout 40%, about 10% to about 35%, about 10% to about 30%, about 10% toabout 25%, about 10% to about 20%, about 10% to about 15%, or a valuewithin one of these ranges. Specific examples may include about 0.01%,about 0.05%, about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%,about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%,about 90%, or a range between any two of these values. The foregoing allrepresenting weight percentages of the pharmaceutical composition. Insome embodiments, the pharmaceutical composition is suitable for topicaladministration. In some embodiments, the pharmaceutical composition issuitable for oral, parenteral (including subcutaneous, intradermal,intramuscular, intravenous, intraarticular, and intramedullary),intraperitoneal, intrathecal, intradural, transmucosal, transdermal,rectal, intranasal, topical (including, for example, dermal, buccal,sublingual and intraocular), intravitreal, or intravaginaladministration.

In some embodiments, the compound is in a therapeutically effectiveamount. In some embodiments, the therapeutically effective amount may beabout 1 mg to about 1000 mg, about 1 mg to about 900 mg, about 1 mg toabout 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg,about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg toabout 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg,about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 100 mgto about 1000 mg, about 200 mg to about 1000 mg, about 300 mg to about1000 mg, about 400 mg to about 1000 mg, about 500 mg to about 1000 mg,about 10 mg to about 500 mg, about 50 mg to about 500 mg, about 100 mgto about 500 mg, about 10 mg to about 300 mg, about 50 mg to about 300mg, from about 100 mg to about 300 mg, about 10 mg to about 150 mg,about 50 mg to about 150 mg, about 60 mg to about 120 mg, about 50 mg toabout 120 mg or a range between any two of these values. Specificexamples include, for example, about 1000 mg, about 900 mg, about 800mg, about 700 mg, about 750 mg, about 600 mg, about 500 mg, about 400mg, about 450 mg, about 300 mg, about 250 mg, about 200 mg, about 175mg, about 150 mg, about 125 mg, about 120 mg, about 110 mg, about 100mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg,about 30 mg, about 20 mg, or any value between the ranges disclosedabove.

In some embodiments, the therapeutically effective amount can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound in a pharmaceuticalcomposition can vary depending upon a number of factors includingdosage, chemical characteristics (e.g., hydrophobicity), and the routeof administration. For example, the compounds can be provided in anaqueous physiological buffer solution containing about 0.1 to about 10%w/v of the compound for parenteral administration. Some typical doseranges for the compounds are from about 1 μg/kg to about 1 g/kg of bodyweight per day. In some embodiments, the dose range is from about 0.01mg/kg to about 100 mg/kg of body weight per day. The dosage is likely todepend on such variables as the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected,composition of the excipient, and its route of administration. Effectivedoses can be extrapolated from dose-response curves derived from invitro or animal model test systems.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.

For preparing solid compositions such as tablets, the principal activeingredient can be mixed with a pharmaceutical excipient to form a solidpre-formulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepre-formulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the pharmaceutical composition sothat the pharmaceutical composition can be readily subdivided intoequally therapeutically effective unit dosage forms such as tablets,pills and capsules. This solid pre-formulation is then subdivided intounit dosage forms of the type described above containing from, forexample, about 0.1 to about 1000 mg of the active ingredient.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the pharmaceutical compositions areadministered by the oral or nasal respiratory route for local orsystemic effect. Compositions in can be nebulized by use of inert gases.Nebulized solutions may be breathed directly from the nebulizing deviceor the nebulizing device can be attached to a face masks tent, orintermittent positive pressure breathing machine. Solution, suspension,or powder compositions can be administered orally or nasally fromdevices which deliver the composition in an appropriate manner.

In some embodiments, the pharmaceutical compositions administered to apatient can be in the form of pharmaceutical compositions describedabove. In some embodiments, these compositions can be sterilized byconventional sterilization techniques, or may be sterile filtered.Aqueous solutions can be packaged for use as is, or lyophilized, thelyophilized preparation being combined with a sterile aqueous carrierprior to administration. In some embodiments, the pH of the compoundpreparations is about 3 to about 11, about 5 to about 9, about 5.5 toabout 6.5, or about 5.5 to about 7.5. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

Methods of Use

The present invention relates to a method of modulating JAK-mediatedfunction in a subject comprising the administration of a therapeuticallyeffective amount of a compound or a pharmaceutical compositioncontaining a compound as disclosed herein.

The present invention also relates to a method of inhibiting aJAK-mediated disease through the interaction between a compounddescribed herein and at least one JAK kinase isoform. This interactionmay result in changes in biochemical output produced by JAK kinases,expression of JAK kinases, binding of JAK kinases with normal bindingpartners, cell phenotype or cell proliferation. These changes may bemonitored to determine the extent of modulation achieved by thecompounds described herein. Such methods may be modes of treatment ofdisease, biological assays, cellular assays, biochemical assays or thelike.

Also provided herein is a method of treating a JAK-mediated diseasecomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound as disclosed herein, a derivativethereof, or a combination thereof. In certain embodiments, thetherapeutically effective amount of a compound as disclosed herein, aderivative thereof, or a combination thereof, may be in the form of apharmaceutical composition. In embodiments, the pharmaceuticalcomposition may include a pharmaceutically acceptable excipient.

In embodiments, diseases or disorders associated with a JAK kinase aretreated by compounds of the present invention include autoimmunedisorders, chronic inflammatory disorders, acute inflammatory disorders,auto-inflammatory disorders, fibrotic disorders, metabolic disorders,neoplasias, or cardiovascular or cerebrovascular disorders. Thus, insome embodiments, the present invention provides a method for treating aJAK-mediated disease or disorder in a patient in need thereof, whereinsaid method comprises administering to said patient a therapeuticallyeffective amount of a provided compound, or composition thereof. SuchJAK-mediated diseases or disorders include, but are not limited to,those described herein.

Some embodiments herein are directed to a method of modulation of anJAK-mediated function in a subject comprising the administration of atherapeutically effective amount of a gut-restricted compound asdisclosed herein. In some embodiments, a method of inhibiting JAK in asubject comprises administering to the subject a gut-restricted compoundof embodiments herein.

The present invention also relates to a method of inhibiting at leastone JAK function comprising the step of contacting JAK kinases with agut-restricted compound as described herein. The cell phenotype, cellproliferation, activity of JAK kinases, change in biochemical outputproduced by active JAK kinases, expression of JAK kinases, or binding ofJAK kinases with a natural binding partner may be monitored. Suchmethods may be modes of treatment of disease, biological assays,cellular assays, biochemical assays, or the like.

Also provided herein is a method of treating a JAK-mediated diseasecomprising administering to a patient in need thereof a therapeuticallyeffective amount of a gut-restricted compound as disclosed herein. Insome embodiments the administering is gut-restricted. In certainembodiments, the therapeutically effective amount of a gut-restrictedcompound as disclosed herein may be in the form of a pharmaceuticalcomposition. In embodiments, the pharmaceutical composition may furtherinclude a pharmaceutically acceptable excipient.

In some embodiments, said JAK-mediated disease or disorder is chosenfrom a skin disorder, pruritus, a hair loss disorder, a cancer, aneoplasm, Alzheimer's disease, an inflammatory condition, connectivetissue diseases and an autoimmune condition.

In certain embodiments, said JAK-mediated disease or disorder is aneoplasm, a malignancy, a myeloproliferative disorder, a hematopoieticneoplasm, a myeloid neoplasm, a lymphoid neoplasm, includingmyelofibrosis, primary myelofibrosis, polycythemia vera, essentialthrombocythemia, acute and chronic leukemias, lymphomas, cutaneouslymphomas including mycosis fungoides, other myeloid malignancies, andmyelodysplastic syndrome.

In certain embodiments, said JAK-mediated disease is selected from thegroup consisting of an autoimmune disorders or responses, broadactivation of the immune responses, bacterial infection, viralinfection, inflammation, a chronic and/or acute inflammatory disorder orcondition, and/or auto-inflammatory disorder, fibrotic disorders,metabolic disorders, a neoplasm, or cardiovascular or cerebrovasculardisorders, a skin disorder, pruritus, a hair loss disorder, a cancer ormalignancy, autoimmune connective tissue diseases and an autoimmunecondition; Still's disease, adult-onset Still's disease, Th17-associatedinflammation, polychondritis (e.g. relapsing polychondritis); myositis,polymyositis, autoimmune myositis, dermatomyositis, juveniledermatomyositis; myasthenia gravis; Arthritis (e.g. rheumatoidarthritis, juvenile rheumatoid arthritis, systemic-onset juvenilerheumatoid arthritis, osteoarthritis, infectious arthritis, inflammatoryarthritis, inflammatory bowel disease-associated arthritis, idiopathicarthritis, juvenile idiopathic arthritis, systemic juvenile idiopathicarthritis, psoriatic arthritis),spondylitis/spondyloarthritis/spondyloarthropathy (ankylosingspondylitis), gout, scleroderma (systemic scleroderma, juvenilescleroderma), Reiter's syndrome/reactive arthritis, Lyme disease,lupus/systemic lupus erythematosus (SLE) (lupus erythematosus, pediatricsystemic lupus erythematosus, cutaneous lupus (subacute cutaneous lupus,chronic cutaneous lupus/discoid lupus, chilblain lupus erythematosus),polymyalgia rheumatica, enthesitis, mixed connective tissue disease,enthesopathy; carditis, myocarditis, angiogenesis disorders,myelodysplastic syndrome, atherosclerosis, restenosis (restenosis of anatherosclerotic coronary artery), acute coronary syndrome, myocardialinfarction, cardiac-allograft vasculopathy, transplant arteriopathy;vasculitis (large vessel vasculitis, small vessel vasculitis, giant-cellarteritis, polyarteritis nodosa, vasculitis syndromes including:Takayasu's arteritis, Wegener's granulomatosis, Behcet's Disease),stimulator of interferon genes (STING) associated vasculopathy withonset in infancy (SAVI); gastrointestinal disorders, enterocolitis,colitis, inflammatory bowel disease (ulcerative colitis, Crohn'sdisease), irritable bowel syndrome, enteritis syndrome/spastic colon,celiac disease; acute and chronic pancreatitis; primary biliarycirrhosis, primary sclerosing cholangitis, jaundice, cirrhosis (forexample, primary biliary cirrhosis or cirrhosis due to fatty liverdisease (for example, alcoholic and nonalcoholic steatosis);esophagitis, gastritis, gastric and duodenal ulcers, peritonitis;Nephropathies: immunologically mediated glomerulonephropathy, autoimmunenephropathy, membranous glomerulopathy, chronic progressivenephropathies, diabetic kidney disease/diabetic nephropathy, renalfibrosis, renal ischemic/reperfusion injury, HIV associated nephropathy,ureteral obstructive nephropathy, glomerulosclerosis, proteinuria,nephrotic syndrome, polycystic kidney disease, autosomal dominantpolycystic kidney disease, a nephropathy is an immunologically mediatednephropathy, autoimmune nephropathy, chronic progressive nephropathies,diabetic nephropathy, renal fibrosis, ischemic/reperfusion injuryassociated, HIV associated nephropathy, ureteral obstructivenephropathy, glomerulonephritis, chronic kidney disease (for example,diabetic nephropathy), hypertension induced nephropathy,glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidneydisease, autosomal dominant polycystic kidney disease, diabetic kidneydisease, lupus nephritis; interstitial cystitis; periodontitis,gingivitis; pulmonary inflammation, sinusitis, pneumonia, bronchitis,asthma, bronchial asthma, allergic asthma, non-allergic asthma, allergicbronchopulmonary mycosis, aspirin-induced asthma, adult-onset asthma,asthma with fixed airflow obstruction, exercise-induced asthma,cough-variant asthma, work-related asthma, nighttime (nocturnal) asthma,asthma with obesity, eosinophilic asthma, steroid-resistantasthma/severe asthma, extrinsic asthma, intrinsic/cryptogenic asthma,Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans, chronicobstructive pulmonary disease (COPD), interstitial lung disease(pulmonary fibrosis, idiopathic pulmonary fibrosis), acute lung injury,pulmonary fibrosis (for example, idiopathic pulmonary fibrosis or cysticfibrosis), chronic obstructive pulmonary disease, adult respiratorydistress syndrome, acute lung injury, drug-induced lung injury;Meniere's disease; ocular disorders including, (e.g.), ocularinflammation, uveitis, dry eye/keratoconjunctivitis sicca, scleritis,episcleritis, keratitis/keratopathy, choroiditis, retinal vasculitis,optic neuritis, retinopathy (diabetic retinopathy, immune mediatedretinopathy, macular degeneration, wet macular degeneration, dry (agerelated) macular degeneration); Mastocytosis, iron deficiency anemia,uremia, hypereosinophilic syndrome (HES), systemic mast cell disease(SMCD), myelodysplastic syndrome, idiopathic thrombocytic purpura; boneresorption diseases; Neurodegenerative disorders,neurological/neuromuscular disorders (e.g.), multiple sclerosis,Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis(ALS) (familial ALS, sporadic ALS), Alzheimer's disease, myastheniagravis, Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barretsyndrome, meningitis, encephalitis, traumatic brain injury; nervoussystem damage, delusional parasitosis, dysregulation of neuronalprocesses and sensory perception, stroke/neuronal ischemia, spinal cordinjury, peripheral neuropathy, tactile hallucinations, spinal cordinjury, psychiatric disease; pain (acute pain, chronic pain, neuropathicpain, or fibromyalgia) paresthetica, nerve irritation, peripheralneuropathy; pruritus/itch (atopic pruritus, xerotic pruritus, pruritusassociated with psoriasis/psoriatic itch/psoriasis-associated itch),acute pruritus, chronic pruritus, idiopathic pruritus, chronicidiopathic itch, biliary itch, hepatobiliary-associated itch, renalassociated itch/renal itch, uremic itch, cholestasis, intrahepaticcholestasis of pregnancy, lichen simplex chronicus associated pruritus,lymphoma-associated itch, leukemia-associated itch, prurigo nodularis,atopic dermatitis-associated itch, atopic itch/atopic pruritus, bullousitch, brachioradial pruritus) neurogenic itch, neuropathic itch,notalgia paresthetica, pruritic popular eruption of HIV, psychogenicitch, swimmer's itch, pruritus or uremic itch, urticarial itch;dermatologic disorders (e.g.), dermatologic drug reactions/drugeruptions, xerosis/dry skin, skin rash, skin sensitization, skinirritation, sunburn, shaving, body louse, head lice/pediculosis, pubiclice, cutaneous larva migrans, scabies, parasitic infection, insectinfestation, urticaria/hives, papular uritcaria, insect bites, insectstings, dandruff, foreign objects or devices on skin, fungal infection,herpes, varicella/chicken pox, eosinophilic folliculitis, dermatosis ofpregnancy/pruritic urticarial papules and plaques of pregnancy (PUPP),inflammatory dermatoses, neutrophilic dermatoses, histiocytoidneutrophilic dermatosis, bowel-bypass syndrome dermatosis,psoriasis/psoriasis vulgaris, lichen planus, lichen sclerosus, acne(acne vulgaris, comedonal acne, inflammatory acne, nodulo-cystic acne,scarring acne, acne keloidalis nuchae), atopies (allergic contactsensitization, allergic dermatitis) dermatitis (atopicdermatitis/eczema, contact dermatitis, photodermatitis, seborrheicdermatitis, stasis dermatitis, acute febrile neutrophilic dermatosis(Sweet's syndrome), chronic atypical neutrophilic dermatosis withlipodystrophy and elevated temperature syndrome (CANDLE Syndrome),hidradenitis suppurativa, hives, pyoderma gangrenosum, alopecia (eyebrowalopecia, intranasal hair alopecia, scarring alopecia (e.g., cicatricialalopecia, central centrifugal cicatricial alopecia, lichen planopilaris,frontal fibrosing alopecia, folliculitis decalvans), nonscarringalopecia (alopecia areata (AA) (patchy AA, alopecia totalis (AT),alopecia universalis (AU), ophiasis pattern alopecia areata, sisaihpopattern alopecia areata)), androgenetic/androgenic alopecia (AGA)/maleand female pattern AGA), telogen effluvium, tinea capitis, hypotrichosis(hereditary hypotrichosis simplex), lichen planopilaris (frontalfibrosing alopecia), punctate palmoplantar keratoderma, erythemaelevatinum diutinum (EED), neutrophilic eccrine hidradenitis, palisadingneutrophilic granulomatous dermatitis, neutrophilic urticarialdermatosis, vitiligo including segmental vitiligo (unisegmentalvitiligo, bisegmental vitiligo, multisegmental vitiligo) non-segmentalvitiligo (acral, facial, or acrofacial vitiligo, centrofacial vitiligo,mucosal vitiligo, confetti vitiligo, trichrome vitiligo, marginalinflammatory vitiligo, quadrichrome vitiligo, blue vitiligo, Koebnerphenomenon, vulgaris vitiligo, generalized vitiligo, universalvitiligo), mixed vitiligo/nonsegmental associated with segmentalvitiligo, focal vitiligo, solitary mucosal vitiligo or vitiligo with orwithout leukotricia (involvement of body hair); bullous diseases,immunobullous diseases (bullous pemphigoid, cicatricial pemphigoid,pemphigus vulgaris, linear IgA disease), gestational pemphigoid,xeroderma pigmentosum; disorders of fibrosis and scarring: fibroids,hepatic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, lowgrade scarring such as, scleroderma, increased fibrosis, keloids,post-surgical scars; wound healing, surgical scarring, radiation inducedfibrosis (for example, head and neck, gastrointestinal or pulmonary),CNS scarring, alimentary track or gastrointestinal fibrosis, renalfibrosis, hepatic or biliary fibrosis, liver fibrosis (for example,nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma),cardiac fibrosis (for example, endomyocardial fibrosis or atrialfibrosis), ophthalmic scarring, fibrosclerosis, scar growth, wound orscab healing, keloid, mediastinal fibrosis, myelofibrosis,retroperitoneal fibrosis/Ormond's disease, progressive massive fibrosis,nephrogenic systemic fibrosis; Sjorgren's syndrome, sarcoidosis,familial Mediterranean fever, Cryopyrin associated periodic syndrome(Muckle-Wells syndrome, familial cold auto-inflammatorysyndrome/familial cold uticaria/TNF receptor associated periodicsyndrome, neonatal-onset multisystem inflammatory disease), hyperoxiainduced inflammations, reperfusion injury, post-surgical trauma, tissueinjury, elevated temperature syndrome; diabetes (Type I diabetes, TypeII diabetes)/diabetes mellitus, Hashimoto's thyroiditis, Graves'disease, Addison's disease, Castleman's disease, hyperparathyroidism,menopause, obesity, steroid-resistance, glucose intolerance, metabolicsyndrome, thyroid illness, hypophysitis; systemic immune senescence;autoimmune atrophic gastritis, autoimmune atrophic gastritis ofpernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis,Goodpasture's disease, Sjogren's syndrome, autoimmune thrombocytopenia,sympathetic ophthalmia; secondary hematologic manifestations ofautoimmune diseases (for example, anemias), autoimmune hemolyticsyndromes (autoimmune hemolytic anemia), autoimmune and inflammatoryhepatitis, autoimmune ovarian failure, autoimmune thrombocytopenia,silicone implant associated autoimmune disease, drug-inducedautoimmunity, HIV-related autoimmune syndromes, metal-inducedautoimmunity, autoimmune deafness, autoimmune thyroid disorders; allergyand allergic reactions including hypersensitivity reactions such as TypeI hypersensitivity reactions, (e.g. including anaphylaxis), Type IIhypersensitivity reactions (e.g. Goodpasture's Disease, autoimmunehemolytic anemia), Type III hypersensitivity reaction diseases (e.g. theArthus reaction, serum sickness), and Type IV hypersensitivity reactions(e.g. contact dermatitis, allograft rejection); acute and chronicinfection, sepsis syndromes (sepsis, septic shock, endotoxic shock,exotoxin-induced toxic shock, gram negative sepsis, gram positivesepsis, fungal sepsis, toxic shock syndrome); acute and chronicinfection, sepsis syndromes (sepsis, septic shock, endotoxic shock,exotoxin-induced toxic shock, gram negative sepsis, gram positivesepsis, fungal sepsis, toxic shock syndrome); a rejection: graft vs.host reaction/graft vs. host disease, allograft rejections (for example,acute allograft rejection or chronic allograft rejection), earlytransplantation rejection; Malignancy, cancer, lymphoma, leukemia,multiple myeloma, a solid tumor, teratoma, metastatic and bonedisorders, internal cancers, cancer of the: bone, mouth/pharynx,esophagus, larynx, stomach, intestine, colon, rectum, lung (for example,non-small cell lung cancer or small cell lung cancer), liver (hepatic),pancreas, nerve, brain (for example, glioma, glioblastoma multiforme,astrocytoma, neuroblastoma, and schwannomas), head and neck, throat,ovary, uterus, prostate, testis, bladder, kidney (renal), breast, gallbladder, cervix, thyroid, prostate, eye (ocular malignancies), and skin(melanoma, keratoacanthoma); as well as fibrotic cancers, fibroma,fibroadenomas, fibrosarcomas, a myeloproliferative disorder, neoplasm(hematopoietic neoplasm, a myeloid neoplasm, a lymphoid neoplasm(myelofibrosis, primary myelofibrosis, polycythemia vera, essentialthrombocythemia)), leukemias (acute lymphocytic leukemia, acute andchronic myelogenous leukemia, chronic lymphocytic leukemia, acutelymphoblastic leukemia, chronic myelomonocytic leukemia (CMML), orpromyelocytic leukemia), multiple myeloma and other myeloid malignancies(myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis(PMF), idiopathic myelofibrosis (IMF)), lymphomas (Hodgkin's disease,cutaneous lymphomas (cutaneous T-cell lymphoma, mycosis fungoides),lymphomas (for example, B-cell lymphoma, T-cell lymphoma, mantle celllymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumors,Hodgkin's disease or non-Hodgkin's disease); Kaposi's sarcoma,rhabdomyosarcoma, seminoma, teratocarcinoma, osteosarcoma, thyroidfollicular cancer; increased accumulation of exogenous opioids orsynthetic opioids, notalgia paraesthetica, obsessive-compulsivedisorders, nostalgia associated with obsessive-compulsive disorders, anda combination thereof.

In some embodiments, additional exemplary disorders include, but are notlimited to: complications from organ transplants (includingxenotransplantation) such as graft vs. host reaction (for example, graftvs. host disease), allograft rejections (for example, acute allograftrejection or chronic allograft rejection), early transplantation,diabetes, a myeloproliferative disorder, a rejection (for example, acuteallograft rejection); bone resorption diseases, asthma (e.g., bronchialasthma), atopy, autoimmune thyroid disorders, chronic atypicalneutrophilic dermatosis with lipodystrophy and elevated temperaturesyndrome (CANDLE Syndrome), SAVI (stimulator of interferon genes (STING)associated vasculopathy with onset in infancy), ulcerative colitis,inflammatory bowel disease, Crohn's disease, celiac disease, ulcerativecolitis, Behcet's disease, myasthenia gravis, nephropathies, andmyocarditis, secondary hematologic manifestations of autoimmune diseases(for example, anemias), autoimmune hemolytic syndromes, autoimmune andinflammatory hepatitis, autoimmune ovarian failure, autoimmune orchitis,autoimmune thrombocytopenia, silicone implant associated autoimmunedisease, drug-induced autoimmunity, HIV-related autoimmune syndromes;acute and chronic infection, sepsis syndromes (e.g.) sepsis, septicshock, endotoxic shock, exotoxin-induced toxic shock, gram negativesepsis, gram positive sepsis, fungal sepsis, toxic shock syndrome;hyperoxia induced inflammations, reperfusion injury, post-surgicaltrauma, tissue injury, pain (e.g.) acute pain, chronic pain, neuropathicpain, or fibromyalgia.

In an embodiment, said asthma is allergic asthma, non-allergic asthma,allergic bronchopulmonary mycosis, aspirin-induced asthma, adult-onsetasthma, asthma with fixed airflow obstruction, exercise-induced asthma,cough-variant asthma, work-related asthma, nighttime (nocturnal) asthma,asthma with obesity, eosinophilic asthma, steroid-resistantasthma/severe asthma, extrinsic asthma, or intrinsic/cryptogenic asthma.

In an embodiment, said vitiligo is segmental vitiligo includingunisegmental, bisegmental or multisegmental vitiligo, non-segmentalvitiligo including acral, facial, or acrofacial vitiligo, centrofacialvitiligo, mucosal vitiligo, confetti vitiligo, trichrome vitiligo,marginal inflammatory vitiligo, quadrichrome vitiligo, blue vitiligo,Koebner phenomenon, vulgaris vitiligo, generalized vitiligo, universalvitiligo, mixed vitiligo (nonsegmental associated with segmentalvitiligo), focal vitiligo, solitary mucosal vitiligo or vitiligo with orwithout leukotricia (involvement of body hair) or any type of vitiligoset forth in Table 1 below:

TABLE 1 Classification of vitiligo. NOMENCLATURE SUBSET NOTESNon-segmental Acrofacial Usually limited to face, head, vitiligo hands,and feet Generalized Symmetrical macules, mainly hands, fingers, face,and trauma- exposed areas Mucosal (at Involvement of the oral and/orleast two sites genital mucosae with other sites involved) of skininvolvement Universal Depigmentation affects 80%-90% of body surface.Segmental vitiligo Unisegmental One or more depigmented maculesdistributed on one side of the body Bisegmental Two segmental lesionsdistributed either unilaterally or bilaterally Plurisegmental Multiplesegmental lesions distributed either unilaterally or bi-laterally Mixedvitiligo Occurrence of SV followed by NSV with a delay SV and NSV of atleast 6 months. At least 20% of a dermatomal segment affected by SV.Unclassified vitiligo Focal vitiligo Isolated macules that do not have asegmental distribution. No evolution into NSV after at least 2 yearsMucosal Exclusive involvement of the oral vitiligo (only or genitalmucosae one site involved)

In an embodiment, said skin disorder is atopic dermatitis, psoriasis,psoriasis vulgaris, skin sensitization, skin irritation, skin rash,contact dermatitis, allergic contact sensitization, allergic dermatitis,inflammatory dermatoses, or neutrophilic dermatoses.

“Pruritus”, as used herein, is interchangeable with “itch.” In someembodiments, pruritus includes chronic idiopathic pruritus, as well aspruritic components of other pruritic disorders. In some embodiments,pruritus may be a symptom of a disease or condition selected from thegroup consisting of: allergic reaction, arthropod bites, athlete's foot,atopic dermatitis (AD), atopic itch, atopic dermatitis-associated itch,autoimmune responses, autoimmune connective tissue disease, bacterialinfection, biliary itch, broad activation of the immune responses, bodylouse, bullous diseases, brachioradial pruritus, brain tumors, chronicidiopathic pruritus, contact dermatitis, cholestasis, cutaneous larvamigrans, cutaneous T-cell lymphoma, nervous system damage, dandruff,delusional parasitosis, dermatomyositis, dermatosis of pregnancy,diabetes mellitus, drug eruptions, dysregulation of neuronal processesand sensory perception, eczema, eosinophilic folliculitis, foreignobjects or devices on skin, fungal infection, gestational pemphigoid,head lice, herpes, hidradenitis suppurativa, hives, Hodgkin's disease,hyperparathyroidism, idiopathic chronic itch, inflammation, insectinfestation, insect bites, insect stings, intrahepatic cholestasis ofpregnancy, iron deficiency anemia, increased accumulation of exogenousopioids or synthetic opioids, internal cancer, jaundice, lichen planus,lichen sclerosus, lupus erythematosus, lymphoma, lymphoma-associateditch, leukemia-associated itch, malignancy, mastocytosis, menopause,multiple sclerosis, neoplasm, nerve irritation, neurogenic itch,neuropathic itch, notalgia paresthetica, notalgia obsessive-compulsivedisorders, paresthetica, parasitic infection, popular urticaria,pediculosis, peripheral neuropathy, photodermatitis, polycythemia vera,psychiatric disease, psychogenic itch, pruritic popular eruption of HIV,pruritic urticarial papules and plaques of pregnancy (PUPPP), psoriasis,psoriasis-associated itch, psoriatic itch, pubic lice, punctatepalmoplantar keratoderma, renal itch, rheumatoid arthritis, scabies,scar growth, shaving, seborrheic dermatitis, stasis dermatitis, sunburn,swimmer's itch, systemic immune senescence, tactile hallucinations,Th17-associated inflammation, thyroid illness, uremia, pruritus oruremic itch, urticaria, urticarial itch, varicella, viral infection,wound or scab healing, and xerosis.

In an embodiment, the hair loss disorder is selected from alopecia,alopecia areata, patchy alopecia areata, alopecia totalis, alopeciauniversalis, ophiasis pattern alopecia areata, sisaihpo pattern alopeciaareata, androgenetic alopecia (male and female pattern hair loss),telogen effluvium, tinea capitis, hypotrichosis, hereditaryhypotrichosis simplex, scarring alopecia, lichen planopilaris, centralcentrifugal cicatricial alopecia, folliculitis decalvans, or frontalfibrosing alopecia.

In an embodiment, the connective tissue disease is selected from SLE(systemic lupus erythematosus), cutaneous lupus (e.g. SCLE, discoidlupus), chilblain lupus erythematosus, myositis, polymyositis,dermatomyositis, scleroderma, Sjogren's syndrome, polychondritis(relapsing polychondritis), vasculitis, or large vessel vasculitis.

In an embodiment, the nephropathy is selected from an immunologicallymediated nephropathy, autoimmune nephropathy, chronic progressivenephropathies, diabetic nephropathy, renal fibrosis,ischemic/reperfusion injury associated, HIV associated nephropathy,ureteral obstructive nephropathy, glomerulosclerosis, proteinuria,nephrotic syndrome, polycystic kidney disease, autosomal dominantpolycystic kidney disease or diabetic kidney disease.

In an embodiment, said cancer is a solid tumor.

In an embodiment, said cancer is prostate cancer, renal cancer, hepaticcancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma,Castleman's disease or pancreatic cancer.

In an embodiment, said cancer is lymphoma, leukemia, or multiplemyeloma.

In an embodiment, said myeloproliferative disorder (MPD) is polycythemiavera (PV), essential thrombocythemia (ET), myeloid metaplasia withmyelofibrosis (MMM), primary myelofibrosis (PMF), chronic myelogenousleukemia (CML), chronic myelomonocytic leukemia (CMML),hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), orsystemic mast cell disease (SMCD).

In an embodiment, said myeloproliferative disorder is myelofibrosis.

In an embodiment, said myeloproliferative disorder is primarymyelofibrosis (PMF).

In some embodiments, the JAK-mediated disease or disorder is a cancer,prostate cancer, renal cancer, hepatic cancer, breast cancer, lungcancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease,pancreatic cancer, lymphoma, leukemia, multiple myeloma, neoplasia,primary malignancies, secondary or recurrent malignancies, metastaticmalignancies, angiogenesis disorders, acute lymphocytic leukemia, acuteand chronic myelogenous leukemia, chronic lymphocytic leukemia, acutelymphoblastic leukemia, promyelocytic leukemia, B-cell lymphoma, T-celllymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma,mast cell tumors, Hodgkin's disease or non-Hodgkin's disease,myelodysplastic syndrome, sarcoma, fibrosarcoma, rhabdomyosarcoma;astrocytoma, neuroblastoma, glioma, schwannoma, non-melanoma skincancers, squamous cell carcinoma, basal cell carcinoma, Merkel cellcarcinoma, seminoma, teratocarcinoma, osteosarcoma, xerodermapigmentosum, keratoacanthoma, thyroid follicular cancer, melanoma,teratoma, rhabdomyosarcoma, metastatic and bone disorders, glioblastomamultiforme, a malignancy, a myeloproliferative disorder, a hematopoieticneoplasm, a myeloid neoplasm, a lymphoid neoplasm, myelofibrosis,primary myelofibrosis, polycythemia vera, essential thrombocythemia,acute and chronic leukemias, lymphomas, cutaneous lymphomas, mycosisfungoides, other myeloid malignancies, myelodysplastic syndrome,myeloproliferative disorder, polycythemia vera, essentialthrombocythemia, myeloid metaplasia with myelofibrosis, primarymyelofibrosis, chronic myelogenous leukemia (CML), chronicmyelomonocytic leukemia, hypereosinophilic syndrome, idiopathicmyelofibrosis (IMF), systemic mast cell disease, and a combinationthereof.

In an embodiment, said bone resorption disease is osteoporosis,osteoarthritis, bone resorption associated with hormonal imbalance, boneresorption associated with hormonal therapy, bone resorption associatedwith autoimmune disease, or bone resorption associated with cancer.

In some embodiments, the JAK-mediated disease or disorder is a fibroticdisorder. Exemplary fibrotic disorders include systemicsclerosis/scleroderma, lupus nephritis, connective tissue disease, woundhealing, surgical scarring, spinal cord injury, CNS scarring, acute lunginjury, pulmonary fibrosis (for example, idiopathic pulmonary fibrosisor cystic fibrosis), chronic obstructive pulmonary disease, adultrespiratory distress syndrome, acute lung injury, drug-induced lunginjury, glomerulonephritis, chronic kidney disease (for example,diabetic nephropathy), hypertension induced nephropathy, alimentarytrack or gastrointestinal fibrosis, renal fibrosis, hepatic or biliaryfibrosis, liver fibrosis (for example, nonalcoholic steatohepatitis,hepatitis C, or hepatocellular carcinoma), cirrhosis (for example,primary biliary cirrhosis or cirrhosis due to fatty liver disease (forexample, alcoholic and nonalcoholic steatosis), radiation inducedfibrosis (for example, head and neck, gastrointestinal or pulmonary),primary sclerosing cholangitis, restenosis, cardiac fibrosis (forexample, endomyocardial fibrosis or atrial fibrosis), ophthalmicscarring, fibrosclerosis, fibrotic cancers, fibroids, fibroma,fibroadenomas, fibrosarcomas, transplant arteriopathy, keloid,mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis,progressive massive fibrosis, and nephrogenic systemic fibrosis.

In some embodiments, the JAK mediated disease or disorder is a metabolicdisorder. Exemplary metabolic disorders include obesity,steroid-resistance, glucose intolerance, and metabolic syndrome. In someembodiments, the JAK-mediated disease or disorder is a neoplasia.Exemplary neoplasias include cancers. In some embodiments the neoplasmsinclude primary malignancies, secondary or recurrent malignancies, ormetastatic malignancies. In some embodiments, exemplary neoplasiasinclude angiogenesis disorders, multiple myeloma, leukemias (forexample, acute lymphocytic leukemia, acute and chronic myelogenousleukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, orpromyelocytic leukemia), lymphomas (for example, B-cell lymphoma, T-celllymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma,mast cell tumors, Hodgkin's disease or non-Hodgkin's disease),myelodysplastic syndrome, sarcoma, fibrosarcoma, rhabdomyosarcoma;astrocytoma, neuroblastoma, glioma and schwannomas; melanoma,non-melanoma skin cancers, (e.g. squamous cell carcinoma, basal cellcarcinoma, Merkel cell carcinoma), seminoma, teratocarcinoma,osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicularcancer, Kaposi's sarcoma, melanoma, teratoma, rhabdomyosarcoma,metastatic and bone disorders, as well as cancer of the bone,mouth/pharynx, esophagus, larynx, stomach, intestine, colon, rectum,lung (for example, non-small cell lung cancer or small cell lungcancer), liver, pancreas, nerve, brain (for example, glioma orglioblastoma multiforme), head and neck, throat, ovary, uterus,prostate, testis, bladder, kidney, breast, gall bladder, cervix,thyroid, prostate, and skin.

In some embodiments, the JAK-mediated disorder is a cardiovascular orcerebrovascular disorder. Exemplary cardiovascular disorders includeatherosclerosis, restenosis of an atherosclerotic coronary artery, acutecoronary syndrome, myocardial infarction, cardiac-allograft vasculopathyand stroke. Exemplary cerebrovascular diseases include central nervoussystem disorders with an inflammatory or apoptotic component,Alzheimer's disease, Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis, spinal cord injury, neuronal ischemia andperipheral neuropathy.

In some embodiments, the JAK-mediated disorder is a gastrointestinaldisorder including, but not limited to, inflammatory bowel disease,Crohn's disease, ulcerative colitis, (e.g., proctosigmoiditis,pancolitis, ulcerative proctitis, left-sided colitis), collagenouscolitis, lymphocytic colitis, immune checkpoint inhibitor inducedcolitis, ileitis, eosinophilic esophagitis, graft vs. host disease,graft versus host disease-related colitis, infectious colitis,indeterminant colitis, atypical colitis, autoimmune enteropathy,irritable bowel syndrome, spastic colitis, acute and chronicpancreatitis, Celiac disease, Behcet's disease, primary biliarycirrhosis, primary sclerosing cholangitis, periodontitis, gingivitis,esophagitis, gastritis, gastric and duodenal ulcers, peritonitis,periodontitis, enteritis, colitis, stomatitis, and stomal/peristomalpyoderma gangrenosum.

In some embodiments, the JAK-mediated disorder is inflammatory boweldisease.

Also provided herein is a compound as disclosed herein for use as amedicament.

Also provided herein is a compound as disclosed herein for use as amedicament for the treatment of a JAK-mediated disease.

Also provided is the use of a compound as disclosed herein as amedicament.

Also provided is the use of a compound as disclosed herein as amedicament for the treatment of a JAK-mediated disease.

Also provided is a compound as disclosed herein for use in themanufacture of a medicament for the treatment of a JAK-mediated disease.

Also provided is the use of a compound as disclosed herein for thetreatment of a JAK-mediated disease.

Also provided herein is a method of inhibition of JAK comprisingcontacting JAK enzyme with a compound as disclosed herein, or aderivative thereof.

In some embodiments, the compound is a gut-restricted compound.

Also provided herein is a method for achieving an effect in a patientcomprising the administration of a therapeutically effective amount of acompound as disclosed herein, or a salt thereof, to a patient, whereinthe effect is chosen from cognition enhancement.

In certain embodiments, the JAK-mediated disease is chosen frompruritus, alopecia, alopecia areata, vitiligo, male pattern androgeneticalopecia, female pattern androgenetic alopecia, atopic dermatitis,rheumatoid arthritis, psoriatic arthritis, and psoriasis.

The compounds can be administered in various modes, e.g. oral,parenteral (including subcutaneous, intradermal, intramuscular,intravenous, intraarticular, and intramedullary), intraperitoneal,intrathecal, intradural, transmucosal, transdermal, rectal, intranasal,topical (including, for example, dermal, buccal, sublingual andintraocular), intravitreal, or intravaginal administration. The specificdose level for any particular patient will depend upon a variety offactors including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination, theprecise disorder being treated, and the severity of the indication orcondition being treated. Also, the route of administration may varydepending on the condition and its severity.

In certain embodiments, a topically or orally administered JAKinhibitor/antagonist described herein for the treatment of alopeciaareata (e.g., patchy alopecia areata, alopecia totalis, alopeciauniversalis) alone or in combination with topical or intralesionalcorticosteroids, topical minoxidil, oral minoxidil, topical or systemicantiandrogens, oral finasteride, oral dutasteride, topical or oralcortexolone 17α-propionate, ketoconazole, spionolactone, prostaglandinF2 analogues (e.g. bimatoprost or latanoprost), contact sensitizationtherapy such as with squaric acid dibutyl ester, dinitrochlorobenzene,diphencyprone, topical or oral methoxalen and ultraviolet a (PUVA),topical anthralin, hair transplantation procedures, microneedling, lowlevel laser light therapy, low level non-laser light therapy,platelet-rich plasma (PRP) therapy or other therapies known to havebeneficial effects in the condition.

In certain embodiments, a topically or orally administered JAKinhibitor/antagonist disclosed herein the treatment of male orfemale-pattern baldness (androgenetic alopecia) alone or in combinationwith topical minoxidil, oral minoxidil, topical or systemicantiandrogens, oral finasteride, oral dutasteride, topical or oralcortexolone 17α-propionate, ketoconazole, spionolactone, prostaglandinF2 analogues (e.g. bimatoprost or latanoprost), contact sensitizationtherapy such as with squaric acid dibutyl ester, dinitrochlorobenzene,diphencyprone, topical or oral methoxalen and ultraviolet a (PUVA),topical anthralin, hair transplantation procedures, microneedling, lowlevel laser light therapy, low level non-laser light therapy,platelet-rich plasma (PRP) therapy or other therapies known to havebeneficial effects in the condition.

In certain embodiments, a topically or orally administered JAKinhibitor/antagonist disclosed herein can be used for the treatment ofscarring alopecia (e.g., cicatricial alopecia, central centrifugalcicatricial alopecia, lichen planopilaris, frontal fibrosing alopecia,folliculitis decalvans) alone or in combination with topical minoxidil,oral minoxidil, topical or systemic antiandrogens, oral finasteride,oral dutasteride, topical or oral cortexolone 17α-propionate,ketoconazole, spionolactone, prostaglandin F2 analogues (e.g.bimatoprost or latanoprost), contact sensitization therapy such as withsquaric acid dibutyl ester, dinitrochlorobenzene, diphencyprone, topicalor oral methoxalen and ultraviolet a (PUVA), topical anthralin, hairtransplantation procedures, microneedling, low level laser lighttherapy, low level non-laser light therapy, platelet-rich plasma (PRP)therapy or other therapies known to have beneficial effects in thecondition.

In certain embodiments, the compounds may be used for the treatment ofvitiligo (e.g., localized vitiligo, focal vitiligo, generalizedvitiligo, segmental vitiligo, acral vitiligo, facial vitiligo,acrofacial vitiligo, mucosal vitiligo, confetti vitiligo, trichromevitiligo, marginal inflammatory vitiligo, quadrichrome vitiligo, bluevitiligo, Koebner phenomenon, vulgaris vitiligo, mixed acrofacial andvulgaris vitiligo, or universal vitiligo) alone or in combination withtopical corticosteroids, topical tacrolimus, topical pimecrolimus,phototherapy such as ultraviolet light therapy with UVB, narrow-bandUVB, oral or topical psoralen plus ultraviolet A (PUVA), calcipotrieneor other topical vitamin D analogs, excimer laser phototherapy, systemicimmunosuppressive agents, surgical treatments such as skin minigrafting,transplantation of autologous epidermal suspension, camouflage such aswith make-up or dihydroxyacetone and such, or other therapies known tohave beneficial effects in the condition.

Specific JAK-mediated diseases to be treated by the compounds,compositions, and methods disclosed herein include a skin disorder,pruritus, cancer, Alzheimer's disease, an inflammatory condition, and anautoimmune condition.

In an embodiment, said skin disorder is pruritus, atopic dermatitis,psoriasis, acne vulgaris, comedonal acne, inflammatory acne,nodulo-cystic acne, scarring acne, hidradenitis suppurativa, pyodermagangrenosum, skin sensitization, skin irritation, skin rash, contactdermatitis or allergic contact sensitization.

Besides being useful for human treatment, certain compounds andcompositions disclosed herein may also be useful for veterinarytreatment of companion animals, exotic animals and farm animals,including mammals, rodents, and the like. More preferred animals includehorses, dogs, and cats.

Combination Therapy

The compounds and pharmaceutical compositions of the present disclosuremay be used to prevent or treat an JAK-mediated disorder by thesequential or co-administration of another pharmaceutical agent.

The compounds of the present invention can be used, alone or incombination with other pharmaceutically active compounds, to treatconditions such as those previously described above. The compound(s) ofthe present invention and other pharmaceutically active compound(s) canbe administered simultaneously (either in the same dosage form or inseparate dosage forms) or sequentially. Accordingly, in one embodiment,the present invention comprises methods for treating a condition byadministering to the subject a therapeutically-effective amount of oneor more compounds of the present invention and one or more additionalpharmaceutically active compounds.

In certain instances, it may be appropriate to administer at least oneof the compounds described herein, or a derivative thereof, incombination with another pharmaceutical agent. By way of example only,if one of the side effects experienced by a patient upon receiving oneof the compounds herein is hypertension, then it may be appropriate toadminister an anti-hypertensive agent in combination with the initialpharmaceutical agent. Or, by way of example only, the therapeuticeffectiveness of one of the compounds described herein may be enhancedby administration of an adjuvant (i.e., by itself the adjuvant may onlyhave minimal therapeutic benefit, but in combination with anotherpharmaceutical agent, the overall therapeutic benefit to the patient isenhanced). Or, by way of example only, the benefit of experienced by apatient may be increased by administering one of the compounds describedherein with another pharmaceutical agent (which also includes atherapeutic regimen) that also has therapeutic benefit. By way ofexample only, in a treatment for diabetes involving administration ofone of the compounds described herein, increased therapeutic benefit mayresult by also providing the patient with another pharmaceutical agentfor diabetes. In any case, regardless of the disease, disorder orcondition being treated, the overall benefit experienced by the patientmay simply be additive of the two pharmaceutical agents or the patientmay experience a synergistic benefit.

Specific, non-limiting examples of possible combination therapiesinclude use of compounds of embodiments herein with: chemotherapeutic oranti-proliferative agent, an anti-inflammatory agent, animmunomodulatory or immunosuppressive agent, a neurotrophic factor, anagent for treating cardiovascular disease, an agent for treatingdiabetes, or an agent for treating immunodeficiency disorders.

Specific, non-limiting examples of possible combination therapies forinflammation include use of certain compounds of the disclosure with:(1) corticosteroids, including but not limited to cortisone,dexamethasone, and methylprednisolone; (2) nonsteroidalanti-inflammatory drugs (NSAIDs), including but not limited toibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (NALFON™),flurbiprofen (ANSAID™), ketoprofen, oxaprozin (DAYPRO™), diclofenacsodium (VOLTAREN™), diclofenac potassium (CATAFLAM™), etodolac(LODINE™), indomethacin (INDOCIN™), ketorolac (TORADOL™), sulindac(CLINORIL™), tolmetin (TOLECTIN™), meclofenamate (MECLOMEN™), mefenamicacid (PONSTEL™), nabumetone (RELAFEN™) and piroxicam (FELDENE™); (3)immunosuppressants, including but not limited to methotrexate(RHEUMATREX™), leflunomide (ARAVA™), azathioprine (IMURAN™),cyclosporine (NEORAL™, SANDIMMUNE™), tacrolimus and cyclophosphamide(CYTOXAN™); (4) CD20 blockers, including but not limited to rituximab(RITUXAN™); (5) Tumor Necrosis Factor (TNF) blockers, including but notlimited to etanercept (ENBREL™), infliximab (REMICADE™) and adalimumab(HUMIRA™); (6) interleukin-1 receptor antagonists, including but notlimited to anakinra (KINERET™); (7) interleukin-6 inhibitors, includingbut not limited to tocilizumab (ACTEMRA™); (8) interleukin-17inhibitors, including but not limited to AIN457; (9) Janus kinaseinhibitors, including but not limited to tasocitinib; and (10) sykinhibitors, including but not limited to fostamatinib.

Specific, non-limiting examples of possible combination therapies forthe treatment of cancer include use of certain compounds of thedisclosure with: (1) alkylating agents, including but not limited tocisplatin (PLATIN™), carboplatin (PARAPLATIN™), oxaliplatin (ELOXATIN™),streptozocin (ZANOSAR™), busulfan (MYLERAN™) and cyclophosphamide(ENDOXAN™); (2) anti-metabolites, including but not limited tomercaptopurine (PURINETHOL™), thioguanine, pentostatin (NIPENT™),cytosine arabinoside (ARA-C™) gemcitabine (GEMZAR™), fluorouracil(CARAC™), leucovorin (FUSILEV™) and methotrexate (RHEUMATREX™); (3)plant alkaloids and terpenoids, including but not limited to vincristine(ONCOVIN™), vinblastine and paclitaxel (TAXOL™); (4) topoisomeraseinhibitors, including but not limited to irinotecan (CAMPTOSAR™),topotecan (HYCAMTIN™) and etoposide (EPOSIN™); (5) cytotoxicantibiotics, including but not limited to actinomycin D (COSMEGEN™),doxorubicin (ADRIAMYCIN™), bleomycin (BLENOXANE™) and mitomycin(MITOSOL™); (6) angiogenesis inhibitors, including but not limited tosunitinib (SUTENT™) and bevacizumab (AVASTIN™); (7) tyrosine kinaseinhibitors, including but not limited to imatinib (GLEEVEC™), erlotinib(TARCEVA™), lapatininb (TYKERB™) and axitinib (INLYTA™); and (8) immunecheckpoint inhibitors, including but not limited to atezolizumab(TECENTRIQ™), avelumab (BAVENCIO™), durvalumab (IMFINZI™), ipilimumab(YERVOY™), pembrolizumab (KEYTRUDA™), nivolumab (OPDIVO™), andtremelimumab.

The compounds and pharmaceutical compositions of the present disclosuremay be used to prevent or treat a JAK-mediated disease by the sequentialor co-administration of another pharmaceutical agent.

In some embodiments, the compounds disclosed in embodiments herein canalso be co-administered (concurrently or sequentially) with a variety ofother pharmaceutical agents or treatments, for example, pharmaceuticalagents or treatments that are administered systemically, such as orallyor parenterally. Examples of such systemic treatments include topical orsystemic corticosteroids (such as prednisone), antibiotics (such aserythromycin, tetracycline, and dicloxacillin), antifungal agents (suchas ketoconazole and fluconazole sold under the tradename Diflucan™),antiviral agents (such as valacyclovir sold under the tradenameValtrex™, acyclovir, and famciclovir sold under the tradename Famvir™),corticosteroids, immunosuppressants (such as cyclophosphamide sold underthe tradename Cytoxan™, azathioprine, methotrexate, mycophenolate),biologics (such as rituximab sold under the tradename Rituxan™,etanercept sold under the tradename Enbrel™, adalimumab sold under thetradename Humira™, infliximab sold under the tradename Remicade™,ustekinumab sold under the tradename Stelara™, and alefacept sold underthe tradename Amevive™), and/or thyroid hormone replacement.

In some embodiments, other therapies that can be used in combinationwith the compounds disclosed herein include, for example,mercaptopurine, topical or systemic corticosteroids such as prednisone,methylprednisolone and prednisolone, alkylating agents such ascyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimusand tacrolimus, inhibitors of inosine monophosphate dehydrogenase(IMPDH) such as mycophenolate, mycophenolate mofetil, azathioprine,various antibodies, for example, antilymphocyte globulin (ALG),antithymocyte globulin (ATG), monoclonal anti-T-cell antibodies (OKT3),and irradiation. These various agents can be used in accordance withtheir standard or common dosages, as specified in the prescribinginformation accompanying commercially available forms of the drugs (seealso, the prescribing information in the 2006 Edition of The Physician'sDesk Reference). In some embodiments, standard dosages of these agentsmay be reduced when used in combination with the compounds ofembodiments herein. Without limiting the scope of this disclosure, it isbelieved the such combination may result in synergistic results withbetter efficacy, less toxicity, longer duration of action, or quickerresponse to therapy. In some embodiments, the combination therapies inembodiments herein may be administered in sub-therapeutic amounts ofeither the compounds of embodiments herein or the additionalpharmaceutical agents, or both. Azathioprine is currently available fromSalix Pharmaceuticals, Inc. under the brand name Azasan™; mercaptopurineis currently available from Gate Pharmaceuticals, Inc. under the brandname Purinethol™; prednisone and prednisolone are currently availablefrom Roxane Laboratories, Inc.; methyl prednisolone is currentlyavailable from Pfizer; sirolimus (rapamycin) is currently available fromWyeth-Ayerst under the brand name Rapamune™; tacrolimus is currentlyavailable from Fujisawa under the brand name Prograf™; cyclosporine iscurrent available from Novartis under the brand name Sandimmune™ andAbbott under the brand name Gengraf™; IMPDH inhibitors such asmycophenolate mofetil and mycophenolic acid are currently available fromRoche under the brand name Cellcept™ and Novartis under the brand nameMyfortic™; azathioprine is currently available from Glaxo Smith Klineunder the brand name Imuran™; and antibodies are currently availablefrom Ortho Biotech under the brand name Orthoclone™, Novartis under thebrand name Simulect™ (basiliximab) and Roche under the brand nameZenapax™ (daclizumab).

In some embodiments, the compounds of embodiments herein areadministered in conjunction, concomitantly or adjunctively, with thepharmaceutical agents or therapies above and/or with a pharmaceuticalagent or therapy for another disease. For example, the compounds ofembodiments herein may be combined with thyroid hormone replacementtherapy or with anti-inflammatory or immunomodulatory therapies.

In some embodiments, the combination therapies in embodiments herein maybe administered in sub-therapeutic amounts of either the compounds ofembodiments herein or the additional pharmaceutical agents, or both.

In any case, the multiple pharmaceutical agents (at least one of whichis a compound disclosed herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple pharmaceutical agentsmay be provided in a single, unified form, or in multiple forms (by wayof example only, either as a single pill or as two separate pills). Oneof the pharmaceutical agents may be given in multiple doses, or both maybe given as multiple doses. If not simultaneous, the timing between themultiple doses may be any duration of time ranging from a few minutes toeight weeks or at any interval appropriate to maintain the desiredtherapeutic efficacy. In some embodiments, the timing between themultiple doses may be a minute, an hour, six hours, a day, two days,three days, four days, five days, six days, a week, two weeks, threeweeks, four weeks, five weeks, six weeks, seven weeks or eight weeks.

Thus, in another aspect, certain embodiments provide methods fortreating JAK-mediated disorders in a human or animal subject in need ofsuch treatment comprising administering to said subject an amount of acompound disclosed herein effective to reduce or prevent said disorderin the subject, in combination with at least one additional agent forthe treatment of said disorder that is known in the art. In a relatedaspect, certain embodiments provide therapeutic compositions comprisingat least one compound disclosed herein in combination with one or moreadditional agents for the treatment of JAK-mediated disorders.

In another embodiment, there is provided a pharmaceutical compositioncomprising one or more compounds of the present invention, one or moreadditional pharmaceutically active compounds, and a pharmaceuticallyacceptable carrier.

In another embodiment, the one or more additional pharmaceuticallyactive compounds is selected from the group consisting ofanti-inflammatory drugs, anti-atherosclerotic drugs, immunosuppressivedrugs, immunomodulatory drugs, cytostatic drugs, anti-proliferativeagents, angiogenesis inhibitors, kinase inhibitors, cytokine blockersand inhibitors of cell adhesion molecules.

In another embodiment, the pharmaceutical compositions can furtherinclude one or more additional pharmaceutical agents such as achemotherapeutic, steroid, anti-inflammatory compound, orimmunosuppressant.

JAK inhibitor compositions described herein are also optionally used incombination with other therapeutic reagents that are selected for theirtherapeutic value for the condition to be treated. In general, thepharmaceutical compositions described herein and, in embodiments wherecombinational therapy is employed, other agents do not have to beadministered in the same pharmaceutical composition, and, because ofdifferent physical and chemical characteristics, are optionallyadministered by different routes. The initial administration isgenerally made according to established protocols, and then, based uponthe observed effects, the dosage, modes of administration and times ofadministration subsequently modified. In certain instances, it isappropriate to administer a JAK inhibitor composition as describedherein in combination with another therapeutic agent. By way of exampleonly, if one of the side effects experienced by a patient upon receivinga JAK inhibitor composition as described herein is rash, then it isappropriate to administer an anti-histamine agent in combination withthe initial therapeutic agent. Or, by way of example only, thetherapeutic effectiveness of a JAK inhibitor is enhanced byadministration of another therapeutic agent (which also includes atherapeutic regimen) that also has therapeutic benefit. In any case,regardless of the disease, disorder or condition being treated, theoverall benefit experienced by the patient is either simply additive ofthe two therapeutic agents or the patient experiences a synergisticbenefit.

Therapeutically effective dosages vary when the drugs are used intreatment combinations. Methods for experimentally determiningtherapeutically effective dosages of drugs and other agents for use incombination treatment regimens are documented methodologies. Combinationtreatment further includes periodic treatments that start and stop atvarious times to assist with the clinical management of the patient. Inany case, the multiple therapeutic agents (one of which is a JAKinhibitor as described herein) are administered in any order, or evensimultaneously. If simultaneously, the multiple therapeutic agents areoptionally provided in a single, unified form, or in multiple forms (byway of example only, either as a single pill or as two separate pills).

In some embodiments, one of the therapeutic agents is given in multipledoses, or both are given as multiple doses. If not simultaneous, thetiming between the multiple doses optionally varies from more than zeroweeks to less than twelve weeks.

In addition, the combination methods and compositions are not to belimited to the use of only two agents, the use of multiple therapeuticcombinations are also envisioned. It is understood that the dosageregimen to treat, prevent, or ameliorate the condition(s) for whichrelief is sought, is optionally modified in accordance with a variety offactors. These factors include the disorder from which the subjectsuffers, as well as the age, weight, sex, diet, and medical condition ofthe subject. Thus, the dosage regimen actually employed varies widely,in some embodiments, and therefore deviates from the dosage regimens setforth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein are optionally a combined dosage form or in separatedosage forms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy areoptionally also administered sequentially, with either agent beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen optionally calls for sequentialadministration of the active agents or spaced-apart administration ofthe separate active agents. The time period between the multipleadministration steps ranges from, a few minutes to several hours,depending upon the properties of each pharmaceutical agent, such aspotency, solubility, bioavailability, plasma half-life and kineticprofile of the pharmaceutical agent. Circadian variation of the targetmolecule concentration is optionally used to determine the optimal doseinterval.

In another embodiment, a JAK inhibitor is optionally used in combinationwith procedures that provide additional or synergistic benefit to thepatient. A JAK inhibitor and the additional therapy(ies) are optionallyadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the pharmaceuticalcomposition containing a JAK inhibitor varies in some embodiments. Thus,for example, a JAK inhibitor is used as a prophylactic and isadministered continuously to subjects with a propensity to developconditions or diseases in order to prevent the occurrence of the diseaseor condition. A JAK inhibitor and compositions are optionallyadministered to a subject during or as soon as possible after the onsetof the symptoms. While embodiments of the present invention have beenshown and described herein, it will be obvious to those skilled in theart that such embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat in some embodiments of the invention various alternatives to theembodiments described herein are employed in practicing the invention.

A JAK inhibitor may be used in combination with drugs from the followingclasses: NSAIDs, immunosuppressive drugs, immunomodulatory drugs,cytostatic drugs, anti-proliferative agents, angiogenesis inhibitors,biological agents, steroids, vitamin D3 analogs, retinoids, other kinaseinhibitors, cytokine blockers, corticosteroids and inhibitors of celladhesion molecules. Where a subject is suffering from or at risk ofsuffering from atherosclerosis or a condition that is associated withatherosclerosis, a JAK inhibitor composition described herein isoptionally used together with one or more agents or methods for treatingatherosclerosis or a condition that is associated with atherosclerosisin any combination. Examples of therapeutic agents/treatments fortreating atherosclerosis or a condition that is associated withatherosclerosis include, but are not limited to any of the following:torcetrapib, aspirin, niacin, HMG CoA reductase inhibitors (e.g.,atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin andsimvastatin), colesevelam, cholestyramine, colestipol, gemfibrozil,probucol and clofibrate.)

Where a subject is suffering from or at risk of suffering from aninflammatory condition, a JAK inhibitor composition described herein isoptionally used together with one or more agents or methods for treatingan inflammatory condition in any combination.

One or more additional pharmaceutical agents such as, for example,anti-inflammatory agents, steroids, immunosuppressants, as well as oneor more other ITK kinase inhibitors and/or other kinase inhibitors, suchas JAK3 kinase, JAK1 kinase, JAK1/2 kinase, or JAK2 kinase inhibitors,such as, for example, those described in WO 99/65909, WO 00/00202,and/or WO/2004/099205, or other agents can be used in combination withthe compounds of the present invention for treatment of JAK-associateddiseases, disorders or conditions.

In certain embodiments, the additional pharmaceutical agent is selectedfrom taxanes, inhibitors of bcr-abl, inhibitors of EGFR, DNA damagingagents, antimetabolites, paclitaxel, imatinib, dasatinib, nilotinib,erlotinib, gefitinib, cisplatin, oxaliplatin, carboplatin,anthracyclines, AraC, 5-FU, camptothecin, doxorubicin, idarubicin,paclitaxel, docetaxel, vincristine, a MEK inhibitor, U0126, a KSPinhibitor, vorinostat, pembrolizumab, nivolumab, atezolizumab, avelumab,tremelimumab, and durvalumab.

In some embodiments, said composition further comprises an additionalpharmaceutical agent selected from a chemotherapeutic oranti-proliferative agent, antiviral, antibiotic, antihistamine, anemollient, systemic phototherapy, psoralen photochemotherapy, lasertherapy, hormone replacement therapy, an anti-inflammatory agent, animmunomodulatory or immunosuppressive agent, a neurotrophic factor, anagent for treating cardiovascular disease, an agent for treatingdiabetes, and an agent for treating immunodeficiency disorders.

In some embodiments, one or more compounds of the embodiments herein canbe used in combination with one or more other therapeutics used in thetreatment of ITK-mediated disorders, and may improve the treatmentresponse as compared to the response to the other therapeutics alone,without exacerbation of its toxic effects. In some embodiments,compounds of embodiments herein can be used in combination with one ormore other ITK inhibitors and/or JAK inhibitors for the treatment ofITK-mediated disorders. Additive or synergistic effects are desirableoutcomes of such combinations. The additional agents can be combinedwith the present compounds in a single or continuous dosage form, or theagents can be administered simultaneously or sequentially as separatedosage forms. In some embodiments, one or more additional agents can beadministered to a patient in combination with at least one JAKinhibitor/antagonist described herein where the additional agents areadministered intermittently as opposed to continuously.

For example, in certain embodiments, a topically or orally administeredJAK inhibitor/antagonist described herein can be used for the treatmentof alopecia areata (e.g. patchy alopecia areata, alopecia totalis,alopecia universalis) alone or in combination with topical orintralesional corticosteroids, topical minoxidil, oral finasteride, oraldutasteride, contact sensitization therapy such as with squaric aciddibutyl ester, dinitrochlorobenzene, diphencyprone, topical or oralmethoxalen and ultraviolet a (PUVA), topical anthralin, hairtransplantation procedures, or other therapies known to have beneficialeffects in the condition.

For example, in certain embodiments, a topically or orally administeredJAK inhibitor/antagonist disclosed herein can be used for the treatmentof male or female-pattern baldness (androgenetic alopecia) alone or incombination with topical minoxidil, oral finasteride (in male), oraldutasteride (in male), topical antiandrogens, hair transplantationprocedures, or other therapies known to have beneficial effects in thecondition.

For example, in certain embodiments, the compounds can be used for thetreatment of vitiligo (e.g. localized vitiligo, focal vitiligo,generalized vitiligo, segmental vitiligo, acral vitiligo, facialvitiligo, acrofacial vitiligo, mucosal vitiligo, confetti vitiligo,trichrome vitiligo, marginal inflammatory vitiligo, quadrichromevitiligo, blue vitiligo, Koebner phenomenon, vulgaris vitiligo, mixedacrofacial and vulgaris vitiligo, or universal vitiligo) alone or incombination with topical corticosteroids, topical tacrolimus, topicalpimecrolimus, phototherapy such as ultraviolet light therapy with UVB,narrow-band UVB, oral or topical psoralen plus ultraviolet A (PUVA),calcipotriene or other topical vitamin D analogs, excimer laserphototherapy, systemic immunosuppressive agents, surgical treatmentssuch as skin minigrafting, transplantation of autologous epidermalsuspension, camouflage such as with make-up or dihydroxyacetone andsuch, or other therapies known to have beneficial effects in thecondition.

In certain embodiments the compounds of the disclosure may be used incombination with one or more agents which act by the same mechanism orby different mechanisms to effect treatment of gastrointestinaldisorders. The different agents may be administered sequentially orsimultaneously (in separate compositions or in the same composition).Useful classes of agents for combination therapy include, but are notlimited to, aminosalicylates, steroids, systemic immunosuppressants,anti-TNFα antibodies, TNF alpha ligand inhibitor, TNF binding agent,anti-VLA-4 antibodies, anti-integrin Cv37 antibodies, anti-bacterialagents, Glucocorticoid agonists, Nuclear factor kappa B inhibitors,5-Lipoxygenase inhibitors, integrin alpha-4/beta-7 antagonist,Cyclooxygenase inhibitors, IL-23 antagonists, Leukotriene BLT receptorantagonist, IL-6 antagonists, IL-8 antagonists, integrin antagonists,nicotinic acetylcholine receptor agonists, PPAR gamma agonists,sphingosine-1-phosphate receptor-1 modulators, B-lymphocyte antigen CD20inhibitors, calcineurin inhibitors, CD3 antagonist, cell adhesionmolecule inhibitors, eosinophil peroxidase inhibitors, heparin agonists,ICAM1 gene inhibitors, IL-13 antagonists, IL-2 receptor alpha subunitinhibitors, insulin sensitizers, interferon beta ligands, interferongamma receptor antagonists, interleukin-1 beta ligand modulators, MAdCAMinhibitors, PDE 4 inhibitors, sphingosine-1-phosphate receptor-1agonists, TLR-9 agonists, acetylcholinesterase inhibitors, ACTH receptoragonists, activin receptor antagonists, CCR5 chemokine antagonists, CCR9chemokine antagonists, and anti-diarrheal medicines.

Aminosalicylates that may be used in combination with the presentlydisclosed compounds include, but are not limited to, mesalamine,osalazine and sulfasalazine. Examples of steroids include, but are notlimited to, prednisone, prednisolone, hydrocortisone, budesonide,beclomethasone, and fluticasone. Systemic immunosuppressants useful fortreatment of inflammatory disorders include, but are not limited tocyclosporine, azathioprine, methotrexate, 6-mercaptopurine, andtacrolimus. Further, anti-TNFα antibodies, which include, but are notlimited to, infliximab, adalimumab, golimumab, and certolizumab, may beused in combination therapy. Useful compounds acting by other mechanismsinclude anti-VLA-4 antibodies, such as natalizumab, anti-integrin α₄β₇antibodies, such as vedolizumab, anti-bacterial agents, such asrifaximin, and anti-diarrheal medicines, such as loperamide. (Mozaffariet al. Expert Opin. Biol. Ther. 2014, 14, 583-600; Danese, Gut, 2012,61, 918-932; Lam et al., Immunotherapy, 2014, 6, 963-971.)

Other compounds that may be used in combination with the presentlydisclosed compounds include, but are not limited to opaganib, abatacept,mongersen, filgotinib, LYC-30937, BI-655130, mirikizumab, adalimumab,tacrolimus, rituximab, GSK-2982772, andecaliximab, naltrexone,risankizumab, QBECO, alicaforsen, etrolizumab, foralumab, ocrelizumab,vedolizumab, amiselimod, ozanimod, dolcanatide, catridecacog,budesonide, STNM-01, cannabidiol, telotristat etiprate, SHP-647,carotegrast methyl, peg-ilodecakin, TOP-1288, iberogast N, PF-06480605,peficitinib, beclomethasone, recombinant interferon beta-1a, infliximab,golimumab, tralokinumab, ustekinumab, certolizumab pegol, thalidomide,upadacitinib, apremilast, natalizumab, interferon beta-1a, rifaximin,RBX-2660, etrasimod, zileuton, fingolimod, cobitolimod, ropivacaine,ABX-464, PF-06700841, prednisolone, GLPG-0974, valganciclovir,ciclosporin, VB-201, tulinercept, MDGN-002, PTG-100, dexamethasone,GED-0507-34-Levo, bertilimumab, brazikumab, KHK-4083, rosiglitazone,mocravimod, sotrastaurin, KAG-308, PUR-0110, E-6007, balsalazide,basiliximab, LP-02, ASP-3291, Trichuris suis ova, K(D)PT, midismase,DNVX-078, vatelizumab, alequel, low molecular weight heparin,metenkefalin, tridecactide, HMPL-004, SB-012, olsalazine, balsalazide,propionyl-L-camitine, Clostridium butyricum, beclomethasone andacemannan.

General Synthetic Methods for Preparing Compounds

Compounds of the present invention can be prepared using methodsillustrated in general synthetic schemes and experimental proceduresdetailed below. General synthetic schemes and experimental proceduresare presented for purposes of illustration and are not intended to belimiting. Starting materials used to prepare compounds of the presentinvention are commercially available or can be prepared using routinemethods known in the art. Representative procedures for the preparationof compounds of the invention are outlined in Schemes 1-4 below.Solvents and reagents, whose synthetic preparations are not describedbelow, can be purchased at Sigma-Aldrich or Fisher Scientific.

Scheme 1 depicts the general synthesis of compounds of Formula (I) whereR₁, R₂, R₃, and R₄ are defined as above, n is 0, 1 or 2, and X is abromo or iodo. PG₁ is an indole protecting group such asbenzenesulfonyl, toluenesulfonyl, mesitylenesulfonyl, t-butylcarbamate(Boc), allyl, benzyl, triisopropylsilyl (TIPS),2-(trimethylsilyl)ethoxymethyl (SEM), or p-methoxybenzyl. PG₂ is asecondary amine protecting group such as t-butylcarbamate (Boc), benzylcarbamate (Cbz), benzyl (Bn), p-methoxybenzyl (PMB), or N-acetyl (Ac).Compound 1b is formed by protecting 1a with an appropriate indoleprotecting group following methods known to those in the art. Couplingof amine 1c with 1b under thermal conditions in a solvent such asN-methyl-2-pyrrolidinone (NMP) in the presence of triethylamine provides1d. Alternatively, Buchwald conditions may be used for the coupling of1b with 1c. Aryl 1e is formed by treating 1d with an arylboronate orheteroarylboronate under Suzuki conditions using a palladium catalyst inthe presence of a base such as cesium carbonate in a dioxane/watersolvent mixture. Deprotection of 1e under standard conditions for theappropriate protecting group (PG₂) provides 1f. Coupling of if with acompound of formula HOR₄ using peptide coupling conditions such as EDCand HOBT or halo-R₄ in the presence of an amine base yields compound 1g.Finally, removal of indole protecting group PG₁ of 1 g provides 1 h.Alternatively, one could remove both protecting groups of 1e and couplethe intermediate with a compound of formula HOR₄ to yield compound 1h.

Scheme 2 depicts the general synthesis of compounds of Formula (I) whereR₁, R₂, R₃, and R₄ are defined as above, n is 0, 1 or 2, and X is abromo or iodo. Compound 2b is formed by protecting 2a with anappropriate indole protecting group. Coupling of amine 2c with 2b underthermal conditions in a solvent such as NMP in the presence oftriethylamine provides 2d. Alternatively, Buchwald conditions may beused for the coupling of 1b with 1c. Aryl 2e is formed by treating 2dwith an arylboronate or heteroarylboronate under Suzuki conditions usinga palladium catalyst in the presence of a base such as cesium carbonatein a dioxane/water solvent mixture. Deprotection of 2e under standardconditions for the appropriate protecting group (PG₁) provides 2f. Insome cases the R₃ substituent on 2d, 2e, or 2f may be modified toprovide a different R₃ group by methods known to those skilled in theart.

Scheme 3 depicts the general synthesis of compounds of Formula (I) whereR₁, R₂, R₃, and R₄ are defined as above, n is 0, 1 or 2, and X is abromo or iodo. Boronate 3a is formed by reacting 1d withbis(pinacolato)diboron (B-Pin) in the presence of a palladium catalystand a ligand such as X-Phos. Aryl 3b is formed by treating 3a with anarylbromide or heteroarylbromide under Suzuki conditions using apalladium catalyst in the presence of a base such as cesium carbonate ina dioxane/water solvent mixture. Deprotection of 3b under standardconditions for the appropriate protecting group (PG₂) provides 3c.Coupling of 3c with a compound of formula HOR₄ using peptide couplingconditions such as EDC and HOBT or halo-R₄ in the presence of an aminebase yields compound 3d. Removal of indole protecting group PG₁ of 3dprovides 3e. Alternatively, one could remove both protecting groups of3b and couple the intermediate with a compound of formula HOR₄ to yieldcompound 3e.

Scheme 4 depicts the general synthesis of compounds of Formula (I) whereR₁, R₂, R₃, and R₄ are defined as above, n is 0, 1 or 2, and X is abromo or iodo. Boronate 4a is formed by reacting 1d with B-Pin in thepresence of a palladium catalyst and a ligand such as X-Phos. Aryl 4b isformed by treating 4a with an arylbromide or heteroarylbromide underSuzuki conditions using a palladium catalyst in the presence of a basesuch as cesium carbonate in a dioxane/water solvent mixture. Removal ofindole protecting group PG₁ of 4b provides 4c.

Exemplary synthetic methods for certain compounds detailed in theexample section are further illustrated by the following.

Example 1: Preparation of(R)-3-oxo-3-(3-((5-(thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile

Step 1: Preparation of5-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

A solution of 5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (6 g, 25.92mmol) in dry dimethylformamide (60 mL) at 0° C. was treated with sodiumhydride (1.65 g, 41.47 mmol, 60% suspension in mineral oil) and thesuspension was stirred for 30 minutes. Then2-(trimethylsilyl)ethoxymethyl chloride (9.56 mL, 53.91 mmol) was addedand the mixture stirred at ambient temperature for 1.5 hours. Thereaction mixture was quenched with saturated ammonium chloride solutionand extracted with ethyl acetate. The combined organic extract waswashed with brine, dried over anhydrous sodium sulfate, the solution wasfiltered and concentrated in vacuo. The crude material was purified bycolumn chromatography (ethyl acetate/hexane) to provide5-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridineas a yellow oil (8.6 g, 92% yield): MS (ES) m/z 361.0 (M+H).

Step 2: Preparation of(R)—N-(1-benzylpiperidin-3-yl)-5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A mixture of5-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(3 g, 8.29 mmol) and (R)-1-benzylpiperidin-3-amine (3.15 g, 16.58 mmol)was heated in a sealed tube to 180° C. After 7 hours the reaction wascooled to room temperature and the crude material was purified by columnchromatography (ethyl acetate/hexane) to provide(R)—N-(1-benzylpiperidin-3-yl)-5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a yellow oil (3.7 g, 45% yield): MS (ES) m/z 517.1 (M+2H).

Step 3: Preparation of ethyl(R)-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(piperidin-3-yl)carbamate

To a stirred solution of(R)—N-(1-benzylpiperidin-3-yl)-5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine(3.7 g, 7.17 mmol) in dry 1,4-dioxane (50 mL) was added ethylchloroformate (1.03 mL, 10.76 mmol) at room temperature and theresulting mixture was heated at 100° C. After 15 hours the reaction wascooled to room temperature and concentrated in vacuo to removevolatiles. The crude material was purified by column chromatography(ethyl acetate/hexane) to provide ethyl(R)-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(piperidin-3-yl)carbamateas a yellow oil (2.7 g, 76% yield): MS (ES) m/z 496.9 (M+H).

Step 4: Preparation of(R)-5-bromo-N-(piperidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

To a stirred solution of ethyl(R)-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(piperidin-3-yl)carbamate(0.5 g, 1.0 mmol) in methanol:water (12 mL:4 mL) was added potassiumhydroxide (2.81 g, 50.25 mmol) and the resulting mixture was subjectedto microwave irradiation at 110° C. for 2 hours. The reaction was cooledto room temperature and diluted with dichloromethane and washed withwater. The organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to provide(R)-5-bromo-N-(piperidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a yellow semisolid (2 g, 94% yield): MS (ES) m/z 424.9 (M+H).

Step 5: Preparation of tert-butyl(R)-3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of(R)-5-bromo-N-(piperidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine(2 g, 4.70 mmol) in dry dichloromethane (30 mL) at 0° C. were added4-dimethylaminopyridine (0.11 g, 0.94 mmol) and triethylamine (1.32 mL,9.4 mmol) followed by di-tert-butyl dicarbonate (1.23 mL, 5.64 mmol).The resulting mixture was stirred at ambient temperature for 15 hours.The reaction mixture was diluted with dichloromethane, washed with waterand brine. The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude material was purified bycolumn chromatography (ethyl acetate/hexane) to provide tert-butyl(R)-3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a yellow oil (1.9 g, 77% yield): MS (ES) m/z 524.9 (M+H).

Step 6: Preparation of tert-butyl(R)-3-((5-(thiazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A solution of tert-butyl(R)-3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.5 g, 0.94 mmol), 4-(tributylstannyl)thiazole (0.46 g, 1.23 mmol) andbis(triphenylphosphine)palladium(II) dichloride (0.13 g, 0.18 mmol) inN-methyl-2-pyrrolidone (10 mL) was heated at 130° C. under a nitrogenatmosphere in sealed tube. After 4 hours the reaction was cooled toambient temperature, diluted with ethyl acetate and filtered throughcelite. The filtrate was washed with water, brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The crude materialwas purified by using flash chromatography (50% ethyl acetate/hexane) toprovide tert-butyl(R)-3-((5-(thiazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a pink gummy solid (0.22 g, 44% yield): MS (ES) m/z 529.9 (M+H).

Step 7: Preparation of(R)—N-(piperidin-3-yl)-5-(thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of tert-butyl(R)-3-((5-(thiazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.21 g, 0.39 mmol) in dichloromethane:trifluoroacetic acid (3.0 mL:3.0mL) was stirred at ambient temperature for 2 hours. The reaction mixturewas concentrated in vacuo, the obtained residue was dissolved in1,4-dioxane:aqueous ammonia (3.0 mL:3.0 mL) and was then stirred atambient temperature overnight. The reaction mixture was concentrated invacuo to provide(R)—N-(piperidin-3-yl)-5-(thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas an off-white solid (0.08 g, 66% yield): MS (ES) m/z 300.0 (M+H).

Step 8: Preparation of(R)-3-oxo-3-(3-((5-(thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile

A solution of cyanoacetic acid (0.024 g, 0.28 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.07 g,0.34 mmol), 1-hydroxybenzotriazole (0.04 g, 0.26 mmol) andN,N-diisopropylethylamine (0.13 mL, 0.68 mmol) in dichloromethane (4 mL)was stirred at ambient temperature for 5 minutes. Then(R)—N-(piperidin-3-yl)-5-(thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.07 g, 0.23 mmol) was added and the resulting mixture was stirred atambient temperature for 18 hours. The reaction mixture was quenched withwater and extracted with dichloromethane. The organic layer was washedwith water, brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (5% methanol/dichloromethane) to provide(R)-3-oxo-3-(3-((5-(thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrileas an off-white solid (0.01 g, 12% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.37 (br s, 1H), 9.20 (br s, 1H), 8.30-8.57 (m, 1H), 7.96 (d, J=14.8Hz, 1H), 7.16 (br s, 1H), 6.60 (s, 1H), 3.92-4.48 (m, 3H), 3.55-3.70 (m,1H), 3.05-3.27 (m, 3H), 1.92-2.33 (m, 2H), 1.46-1.75 (m, 3H); MS (ES)m/z 366.9 (M+H).

Example 2: Preparation of(R)-3-(3-((5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of tert-butyl(R)-3-((5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A mixture of tert-butyl(R)-3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.4 g, 0.76 mmol, as prepared by the method described in Scheme 5,step-5),1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.24 g, 0.10 mmol), bis-(triphenylphosphine)palladium(II) dichloride(0.11 g, 0.15 mmol) and 2M aqueous solution of potassium phosphatetribasic (0.48 g. 2.28 mmol) in 1,4-dioxane (20 mL) was heated at 80° C.overnight under a nitrogen atmosphere. The reaction mixture was cooledto ambient temperature, diluted with ethyl acetate and filtered throughcelite. The filtrate was washed with water, brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The crude materialwas purified by using flash chromatography (50% ethyl acetate in hexane)to provide tert-butyl(R)-3-((5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas an orange-colored gummy solid (0.34 g, 80% yield): MS (ES) m/z 562.9(M+H).

Step 2: Preparation of(R)-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

(R)-5-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-aminewas prepared by the method described in Example 1, step-7 and isolatedas a pale yellow gum (0.23 g, 98%): MS (ES) m/z 333.0 (M+H)⁺.

Step 3: Preparation of(R)-3-(3-((5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

(R)-3-(3-((5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrilewas prepared by the method described in Example 1, Step-8 to give anoff-white solid (0.05 g, 18% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.46(br s, 1H), 8.41-8.46 (m, 2H), 8.28-8.31 (m, 1H), 7.60-7.91 (m, 1H),7.10-7.20 (m, 2H), 6.65 (s, 1H), 4.40 (s, 1H), 3.91-4.18 (m, 3H),3.43-3.68 (m, 2H), 3.18-3.26 (m, 1H), 2.06-2.07 (m, 1H), 1.57-1.77 (m,3H); MS (ES) m/z 399.9 (M+H).

Analytical Conditions:

Column: Kinetex C18 (100 mm×4.6 mm×2.6 μm)

Mobile phase(A): 0.1% TFA acid in Water

Mobile phase(B): ACN

Flow rate: 0.75 mL/min

Example 3: Preparation of(R)-3-(3-((5-(2-methylthiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of tert-butyl(R)-3-((5-(2-methylthiazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A solution of tert-butyl(R)-3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.2 g, 0.38 mmol, as prepared by the method described in Scheme-1,step-5), in 1,4-dioxane:water (4.5 mL:0.5 mL) was treated with potassiumcarbonate (0.16 g, 0.76 mmol) followed by2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (0.17g, 0.76 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane(0.03 g, 0.04 mmol). The resulting mixture was heated in a sealed tubeat 100° C. for 16 hours under a nitrogen atmosphere. The reaction wascooled to ambient temperature, diluted with ethyl acetate and water. Theorganic layer was separated, washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography (40% ethyl acetate/hexane) toprovide tert-butyl(R)-3-((5-(2-methylthiazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a brown liquid (0.15 g, 36% yield): MS (ES) m/z 543.9 (M+H).

Step 2: Preparation of(R)-5-(2-methylthiazol-5-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

(R)-5-(2-Methylthiazol-5-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-aminewas prepared by the method described in Example-1, Step-7 which wasisolated as a pale yellow gum (0.13 g, 94% yield): MS (ES) m/z 314.0(M+H)⁺.

Step 3:(R)-3-(3-((5-(2-methylthiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

(R)-3-(3-((5-(2-methylthiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrilewas prepared by the method as described in Example 1, Step-8 to give anoff-white solid (0.01 g, 5% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.43(s, 1H), 7.77-7.75 (m, 1H), 7.59-7.57 (m, 1H), 7.22 (s, 1H), 6.61-6.57(m, 1H), 5.16-5.14 (m, 1H), 4.16-4.13 (m, 1H), 4.03 (s, 2H), 3.89-3.77(m, 3H), 2.67-2.65 (m, 3H), 1.96 (s, 2H), 1.60-1.57 (m, 3H); MS (ES) m/z381.3 (M+H). HPLC purity: 98.58%

Analytical Conditions:

Column: X bridge (250 mm×4.6 mm×5 mic)

Mobile phase(A): 0.1% Ammonia in water

Mobile phase(B): Methanol

Flow rate: 1.0 mL/min

Example 4: Preparation of(R)-3-oxo-3-(3-((5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile

Step 1: Preparation of2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole

A solution of5-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(1.5 g, 4.15 mmol, prepared by the method described in Scheme 1,step-1), 2-(tributylstannyl)thiazole (1.7 g, 4.57 mmol) andbis(triphenylphosphine)palladium(II) dichloride (0.58 g, 0.83 mmol) inN-methyl-2-pyrrolidone (15 mL) was heated at 130° C. in a sealed tubeunder a nitrogen atmosphere. After 4 hours the reaction mixture wascooled to ambient temperature, diluted with ethyl acetate and filteredthrough celite. The filtrate was washed with water, brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by using flash chromatography (10% ethyl acetatein hexane) to provide 2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole as a colorless oil(0.75 g, 49% yield): MS (ES) m/z 365.8 (M+H).

Step 2: Preparation of tert-butyl(R)-3-((5-(thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A solution of2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole(0.7 g, 1.92 mmol), tert-butyl (R)-3-aminopiperidine-1-carboxylate (0.57g, 2.87 mmol) and triethylamine (0.27 mL, 1.92 mmol) inN-methyl-2-pyrrolidone (10 mL) was subjected to microwave irradiation at130° C. for 3 hours. The reaction was cooled to ambient temperature,diluted with ethyl acetate, washed with water, brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by using flash chromatography (50% ethyl acetatein hexane) to provide tert-butyl(R)-3-((5-(thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a pale yellow solid (0.24 g, 24% yield): MS (ES) m/z 529.9 (M+H).

Step 3: Preparation of(R)—N-(piperidin-3-yl)-5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

(R)—N-(Piperidin-3-yl)-5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-aminewas prepared by the method described in Example 1, step-7 which wasisolated as an off-white solid (0.11 g, 81% yield): MS (ES) m/z 300.0(M+H)⁺.

Step 4: Preparation of(R)-3-oxo-3-(3-((5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile

(R)-3-Oxo-3-(3-((5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrilewas prepared by the method described in Example 1, Step-8 to give ayellow solid (0.05 g, 38% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.44 (brs, 1H), 9.75 (br s, 1H), 7.41 (d, J=10.4 Hz, 1H), 7.74-7.80 (m, 1H),7.59 (s, 1H), 7.22 (s, 1H), 6.69 (s, 1H), 4.15-4.45 (m, 1H), 3.90-4.10(m, 2H), 3.61-3.82 (m, 1H), 3.25-3.55 (m, 2H), 1.95-2.20 (m, 2H),1.45-1.85 (m, 3H); MS (ES) m/z 366.9 (M+H).

Example 5: Preparation of(R)-3-(3-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole

A mixture of5-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(2 g, 5.54 mmol, prepared by the method described in Scheme 5, step-1),potassium tert-butoxide (1.24 g, 11.08 mmol)bis(triphenylphosphine)palladium(II) dichloride (0.19 g, 0.27 mmol) andoxazole (0.68 g, 9.97 mmol) in 1,4-dioxane (20 mL) was heated in asealed tube to 110° C. under nitrogen. After 5 hours the reaction wascooled to ambient temperature, diluted with water and extracted withethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography (ethyl acetate/hexane) to provide2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazoleas an off-white solid (0.43 g, 22% yield): MS (ES) m/z 349.9 (M+H).

Step 2: Preparation of tert-butyl(R)-3-((5-(oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole(0.43 g, 1.28 mmol), triethylamine (0.03 mL, 0.24 mmol) and tert-butyl

-   -   (R)-3-aminopiperidine-1-carboxylate (0.464 g, 2.32 mmol) in        N-methylpyrrolidone (4 mL) was subjected to microwave        irradiation at 130° C. for 5 hours. The reaction was cooled to        ambient temperature, diluted with water and extracted with ethyl        acetate. The organic layer was washed with brine, dried over        sodium sulfate, filtered and concentrated in vacuo. The crude        material was purified by flash chromatography (50% ethyl        acetate/hexane) to provide tert-butyl        (R)-3-((5-(oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate        as an off-white solid (0.35 g, 53%): MS (ES) m/z 514.0 (M+H).

Step 3: Preparation of(R)-5-(oxazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

(R)-5-(Oxazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-aminewas prepared by the method as described in Example 1, step-7: MS (ES)m/z 284.1 (M+H).

Step 4: Preparation of(R)-3-(3-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

(R)-3-(3-((5-(Oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrilewas prepared by the method as described in Example 1, Step-8 to give anoff-white solid (0.05 g, 27% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.61(br s, J=8.8 Hz, 1H), 9.11-9.05 (m, 1H), 8.53 (d, J=6.8 Hz, 1H), 8.10(s, 1H), 7.33-7.22 (m, 2H), 6.69 (s, 1H), 4.37 (br s, 1H), 4.17-3.58 (m,6H), 2.04 (s, 1H), 1.73-1.54 (m, 3H); MS (ES) m/z 351.1 (M+H).

Example 6: Preparation of(R)-3-(3-((5-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of ethyl(R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution ethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.2 g, 0.89 mmol),triethylamine (0.06 mL, 0.44 mmol) and benzyl(R)-3-aminopiperidine-1-carboxylate (0.31 g, 1.33 mmol) inN-methylpyrrolidone (1 mL) was subjected to microwave irradiation at165° C. for 2 hours. The reaction was cooled to ambient temperature,diluted with water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (40% ethyl acetate/hexane) to give ethyl(R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a pale yellow solid (0.25 g, 67%): MS (ES) m/z 422.9 [M+H]⁺.

Step 2: Preparation of(R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid

To a stirred solution of propyl ethyl(R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(1.5 g, 3.55 mmol) in ethanol (20 mL) at 0° C. was added sodiumhydroxide (5N, 10 mL) and the mixture was stirred at ambient temperaturefor 12 hours. The reaction mixture was concentrated in vacuo and theresidue was dissolved in water and washed with diethyl ether. Theaqueous layer was acidified to pH-2.0 with saturated potassium bisulfatesolution at 0° C. and then extracted with 5% methanol/dichloromethane.The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The obtained crude product was triturated withn-pentane to provide(R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid as an off-white solid (1.10 g, crude): MS (ES) m/z 394.9 (M+H).

Step 3: Preparation of benzyl(R,E)-3-((5-((1-aminoethylidene)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of(R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic(0.5 g, 1.26 mmol) in N,N-dimethylformamide (10 mL) was added1-bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphate (0.53 g, 1.39 mmol), N,N-diisopropylethylamine (1.2g, 1.73 mmol) and acetamidine hydrochloride (0.178 g, 1.90 mmol). Themixture was stirred at ambient temperature for 18 hours. The reactionmixture was filtered and concentrated in vacuo to provide benzyl(R,E)-3-((5-((1-aminoethylidene)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a white solid (0.4 g, crude): MS (ES) m/z 435.0 (M+H).

Step 4: Preparation of benzyl(R)-3-((5-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A stirred solution of benzyl(R,E)-3-((5-((1-aminoethylidene)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.1 g, 0.23 mmol) and hydroxylamine hydrochloride (0.024 g, 0.345mmol), in acetic acid (0.2 mL) was heated to 90° C. After 3 hours thereaction mixture was cooled to ambient temperature, quenched with waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The crude material was purified by flash chromatography (5%methanol/dichloromethane) to provide benzyl(R)-3-((5-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a white solid (0.01 g, 10% yield): MS (ES) m/z 433.3 (M+H).

Step 5: Preparation of(R)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-aminehydrochloride

A stirred solution of benzyl(R)-3-((5-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.34 g, 0.78 mmol) and conc. HCl (3 mL) in a sealed tube was heated at70° C. After 3 hours the reaction was cooled to room temperature andconcentrated in vacuo to provide((R)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas an off-white solid (0.25 g, crude): MS (ES) m/z 299.0 (M+H).

Step 6: Preparation of(R)-3-(3-((5-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

To a stirred solution((R)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.25 g, 0.83 mmol) in N,N-dimethylformamide (0.5 mL) was added1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.34 g, 0.91 mmol),N,N-diisopropylethylamine (1.2 g, 1.73 mmol) and cyanoacetic acid (0.118g, 1.25 mmol). The mixture was stirred at ambient temperature for 18hours. The reaction mixture was concentrated in vacuo and the crudematerial was purified by flash chromatography (5%methanol/dichloromethane) to provide(R)-3-(3-((5-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.04 g, 13% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.82 (br s, 1H), 8.71-8.76 (m, 1H), 8.56-8.57 (m, 1H), 7.28 (s, 1H),6.74 (s, 1H), 4.50 (br s, 1H), 4.28 (br s, 1H), 4.03-4.14 (m, 1H),3.82-3.91 (m, 1H), 3.57-3.60 (m, 1H), 3.39 (m, 2H), 3.29 (m, 1H),2.39-2.41 (m, 3H), 2.04 (m, 1H), 1.56-1.78 (m, 2H); MS (ES) m/z 365.9(M+H).

Example 7: Preparation of(R)-3-(3-((5-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of benzyl(R)-3-((5-(hydrazinecarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of ethyl(R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.5 g, 1.18 mmol, prepared by the method as described in Example 6,step-1) and hydrazine hydrate (32 mL) in ethanol (8 mL) was heated at110° C. for 18 hours. After cooling to room temperature the mixture wasconcentrated in vacuo to remove volatiles and the residue was trituratedwith 10% methanol in diethyl ether to provide benzyl(R)-3-((5-(hydrazinecarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a yellow solid (0.3 g, 62% yield): MS (ES) m/z 409.2 (M+H).

Step 2: Preparation of benzyl(R)-3-((5-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of benzyl(R)-3-((5-(hydrazinecarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.1 g, 0.24 mmol) and triethylorthoformate (2 mL, 12.0 mmol) in ethanol(8 mL) was heated in a sealed tube to 120° C. After 18 hours thereaction was cooled to room temperature and the mixture was concentratedin vacuo to remove volatiles. The crude material was purified by columnchromatography (methanol/dichloromethane) to provide benzyl(R)-3-((5-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a pale yellow solid (0.16 g, 40% yield): MS (ES) m/z 419.2 (M+H).

Step 3: Preparation of(R)-5-(1,3,4-oxadiazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

To a solution of benzyl(R)-3-((5-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.16 g, 0.38 mmol) in tetrahydrofuran:ethanol (8 mL:5 mL) was added 10%palladium on carbon (0.03 g) and the heterogeneous mixture was stirredat ambient temperature under hydrogen atmosphere for 32 hours. Thereaction mixture was filtered through celite and washed with methanol.The filtrate was concentrated in vacuo to provide crude material whichwas triturated with diethyl ether to provide(R)-5-(1,3,4-oxadiazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a yellow solid (0.05 g, 52% yield): MS (ES) m/z 285.2 (M+H).

Step 4: Preparation of(R)-3-(3-((5-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

(R)-3-(3-((5-(1,3,4-Oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrilewas prepared by the method as described in Example 1, Step-8 to give apale brown solid (0.01 g, 14% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.77(s, 1H), 9.24 (s, 1H), 8.40-8.47 (m, 2H), 7.28 (s, 1H), 6.75 (s, 1H),4.20 (d, J=10.0 Hz, 1H), 4.04 (q, JI=18.8 Hz, J2=18.4 Hz, 2H), 3.73-3.84(m, 2H), 3.47 (d, J=10.0 Hz, 1H), 3.14 (d, J=4.8 Hz, 1H), 2.11 (bs, 1H),1.98 (t, J=8.0 Hz, 1H), 1.70-1.75 (m, 2H); MS (ES) m/z 352.0 (M+H).

Analytical Conditions:

Column: Inertsil ODS 3V (250 mm×4.6 mm×5 mic)

Mobile phase(A): 0.1% Ammonia in water

Mobile phase(B): ACN

Flow rate: 1.0 mL/min

Composition of B: 0/10, 12/70, 25/90, 27/10, 30/10

Example 8: Preparation of(R)-3-(3-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of ethyl4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of ethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (5 g, 22.2 mol) in drydimethylformamide (20 mL) at 0° C. was added sodium hydride (1.42 g,35.6 mol, 60% suspension in mineral oil) and the suspension was stirredfor 30 minutes. Then 2-(trimethylsilyl)ethoxymethyl chloride (7.88 mL,44.5 mol) was added and the resulting mixture was stirred at ambienttemperature for 1.5 hours. The reaction mixture was quenched withsaturated ammonium chloride solution and extracted with ethyl acetate.The combined organic extract was washed with brine, dried over anhydroussodium sulfate, the solution was filtered, and concentrated in vacuo.The crude material was purified by column chromatography (ethylacetate/hexane) to provide ethyl4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a yellow oil (5.5 g, 70% yield): MS (ES) m/z 354.9 (M+H).

Step 2: Preparation of ethyl(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(2.0 g, 5.64 mmol) in N-methyl-2-pyrrolidone (20 mL) was addedtert-butyl (R)-3-aminopiperidine-1-carboxylate (1.7 g, 2.11 mmol)followed by triethylamine (0.8 mL) in a sealed tube. The mixture washeated to 135° C. for 3 hours. After cooling to ambient temperature, thereaction mixture was quenched with water and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography (17% ethyl acetate/hexane) toprovide ethyl

-   -   (R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate        as a colorless oil (1.0 g, 35% yield): MS (ES) m/z 519.0 [M+H]⁺.

Step 3: Preparation of(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid

To a stirred solution of ethyl(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.0 g, 1.93mmol) in methanol (3 mL), tetrahydrofuran:water (3 mL:3 mL) was addedsodium hydroxide (0.15 g, 3.85 mmol) at ambient temperature. The mixturewas stirred at 60° C. for 8 hours. The reaction was cooled to ambienttemperature and concentrated in vacuo to remove volatiles. The residuewas dissolved in water and acidified with 1N HCl and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudematerial was triturated with n-pentane to provide(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid as an off-white solid (0.8 g, 84% yield): MS (ES) m/z 490.9 [M+H]⁺.

Step 4: Preparation of tert-butyl(R)-3-((5-(2-formylhydrazine-1-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a solution of(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (0.4 g, 0.752 mmol) in dimethylformamide (5 mL) was added formicacid hydrazide (0.07 g, 1.13 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.15 g, 0.37 mmol) andN,N-disopropylethylamine (0.07 mL, 0.376 mmol) and the mixture wasstirred at ambient temperature for 3 hours. The reaction was quenchedwith water and extracted with ethyl acetate. The organic layer waswashed with sodium bicarbonate solution, brine, dried over anhydroussodium sulfate. The solution was filtered and concentrated in vacuo toprovide tert-butyl(R)-3-((5-(2-formylhydrazine-1-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a pale yellow liquid (0.4 g, 90% yield): MS (ES) m/z 533.0 [M+H]⁺.

Step 5: Preparation of tert-butyl(R)-3-((5-(1,3,4-thiadiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a solution of tert-butyl(R)-3-((5-(2-formylhydrazine-1-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.37 g, 0.695 mmol) in tetrahydrofuran (20 mL) was added Lawesson'sreagent (0.84 g, 2.08 mmol) at ambient temperature and the mixture wasstirred at 70° C. for 16 hours. The reaction was cooled to ambienttemperature quenched with 10% citric acid and the solution was stirredfor 5 minutes followed by the addition of sodium bicarbonate solutionand stirred for another 10 minutes. The aqueous layer was extracted withethyl acetate, washed with saturated sodium bicarbonate and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (35% ethyl acetate/hexane) to provide tert-butyl(R)-3-((5-(1,3,4-thiadiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a pale yellow liquid (0.28 g, 78% yield): MS (ES) m/z 530.9 [M+H]⁺.

Step 6: Preparation of(R)—N-(piperidin-3-yl)-5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

(R)—N-(Piperidin-3-yl)-5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-aminewas prepared by the method as described in Example 1, Step-7 to give ayellow liquid (0.2 g, % yield): MS (ES) m/z 301.2 [M+H]⁺.

Step 7:(R)-3-(3-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

(R)-3-(3-((5-(1,3,4-Thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrilewas prepared by the method as described in Example 1, Step-8 to give anoff-white solid (0.05 g, 20% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.71(s, 1H), 9.4-9.5 (m, 2H), 8.35 (d, J=6.4 Hz, 1H), 7.25 (s, 1H), 6.78 (s,1H), 4.39 (s, 1H), 3.60-4.21 (m, 6H), 2.09 (s, 1H), 1.65-1.74 (m, 3H);MS (ES) m/z 351.3 (M+H).

Example 9 and 10: Preparation of3-((3R,5S)-3-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileand3-((3S,5R)-3-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Benzyl 3-amino-5-methylpiperidine-1-carboxylate hydrochloride wasprepared by the method described below.

Step 1: Preparation of tert-butyl (5-methylpiperidin-3-yl)carbamate

In a Parr shaker vessel, a stirred solution of tert-butyl(5-methylpyridin-3-yl)carbamate (0.8 g) in acetic acid (30 mL) was addedplatinum dioxide (0.2 g) and rhodium on carbon (0.2 g) under a nitrogenatmosphere. The reaction mixture was stirred under hydrogen (100 psi) atambient temperature for 24 hours. The mixture was filtered throughcelite and the filtration concentrated in vacuo to provide tert-butyl(5-methylpiperidin-3-yl)carbamate as a glassy liquid (0.74 g, 90%yield): MS (ES) m/z 215.1 [M+H]⁺.

Step 2: Preparation of benzyl3-((tert-butoxycarbonyl)amino)-5-methylpiperidine-1-carboxylate

To a stirred solution of tert-butyl (5-methylpiperidin-3-yl)carbamate(1.5 g, 6.99 mmol) in tetrahydrofuran (12 mL) and water (3 mL), wasadded sodium hydroxide (1.4 g, 34.99 mmol) and benzyl chloroformate,(2.4 mL, 13.99) at 0° C. The mixture was stirred at ambient temperaturefor 16 hours. The reaction mixture was diluted with ethyl acetate,washed with brine, dried over sodium sulfate, filtered and concentratedin vacuo. The crude material was purified by flash chromatography (23%ethyl acetate/hexane) to provide benzyl3-((tert-butoxycarbonyl)amino)-5-methylpiperidine-1-carboxylate as awhite solid (0.8 g, 33% yield): MS (ES) m/z 293.2 [M−56]⁺.

Step 3: Preparation of benzyl 3-amino-5-methylpiperidine-1-carboxylatehydrochloride

To a stirred solution of benzyl3-((tert-butoxycarbonyl)amino)-5-methylpiperidine-1-carboxylate (0.8 g)in dichloromethane (20 mL), was added 4M hydrochloric acid in1,4-dioxane (8 mL) at 0° C. The reaction mixture was stirred for 3 hoursat ambient temperature then concentrated in vacuo to provide benzyl3-amino-5-methylpiperidine-1-carboxylate hydrochloride as a white solid(0.54 g, 95% yield): MS (ES) m/z 249.0 [M+H]⁺.

Step 1: Preparation of benzyl3-methyl-5-((5-(oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole(0.35 g, 1.00 mmol, prepared by the method described in Example 5,Step-1), triethylamine (0.4 mL, 3.00 mmol) benzyl3-amino-5-methylpiperidine-1-carboxylate hydrochloride (0.43 g, 1.50mmol) in N-methylpyrrolidone (10 mL) was subjected to microwaveirradiation at 135° C. for 5 hours. The reaction was cooled to ambienttemperature, diluted with water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over sodium sulfate, filteredand concentrated in vacuo. The crude material was purified by flashchromatography (21% ethyl acetate/hexane) to provide benzyl3-methyl-5-((5-(oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a thick brown liquid (0.13 g, 23%): MS (ES) m/z=561.9 [M+H]⁺.

Step 2: Preparation ofN-(5-methylpiperidin-3-yl)-5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of benzyl3-methyl-5-((5-(oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.13 g, 0.23 mmol) in trifluoroacetic acid (3.0 mL) was stirred at 100°C. for 1 hour. After cooling the reaction mixture was concentrated invacuo, the obtained residue was dissolved in 1,4-dioxane:aqueous ammonia(5.0 mL:5.0 mL) and was then stirred at ambient temperature overnight.The reaction mixture was concentrated in vacuo to provideN-(5-methylpiperidin-3-yl)-5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas thick liquid (0.08 g, crude): MS (ES) m/z 298.0 [M+H]⁺.

Step 3: Preparation of3-(3-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

To a solution ofN-(5-methylpiperidin-3-yl)-5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.07 g, 0.235 mmol) in dichloromethane (10 mL) was added triethylamine(0.1 mL, 0.706 mmol), propanephosphonic acid anhydride (0.4 mL, 0.706mmol) and cyanoacetic acid (0.03 g, 0.353 mmol) at 0° C. The reactionmixture was stirred at ambient temperature for 3 hours. The reactionmixture was quenched with water and extracted with dichloromethane. Theorganic layer was washed with water, brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (70% ethyl acetate/hexane) to provideracemic3-(3-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.025 g, 31% yield): MS (ES) m/z 351.1 [M+H]⁺.

The racemic compound was further purified by chiral preparative HPLC toseparate the enantiomers.

Chiral HPLC

Analytical Conditions:

Column: CHIRALPAC IC (10 mm×4.6 mm×3 mic)

Mobile phase(A): n-hexane: ethanol with 0.1% DEA (80:20)

Flow rate: 1.0 mL/min

Example 9:3-((3R,5S)-3-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile(stereochemistry has been provisionally assigned)

Isolated as a white solid, (0.028 g, 11% yield): ¹H NMR (400 MHz, CDCl₃)δ 11.84 (s, 1H), 10.37-10.35 (m, 1H), 8.56 (m, 2H), 7.75 (s, 1H), 6.975(m, 2H), 5.12 (d, J=12.4 Hz, 1H), 4.2 (br s, 1H), 3.75-2.00 (m, 7H),1.49 (s, 1H), 0.96 (d, 3H); MS (ES) m/z=365.2 [M+H]⁺; HPLC Purity:99.45%. Retention time 11.4 min.

Example 10:3-((3S,5R)-3-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile(stereochemistry has been provisionally assigned)

Isolated as a white solid, (0.003 g, 13% yield): ¹H NMR (400 MHz, CDCl₃)δ 11.86 (s, 1H), 10.37-10.35 (m, 1H), 8.56 (m, 2H), 7.75 (s, 1H), 6.98(m, 2H), 5.12 (d, J=12.4 Hz, 1H), 4.18 (br s, 1H), 3.8-2.20 (m, 7H),2.00 (s, 1H), 0.9 (d, 3H); MS (ES) m/z=365.1 [M+H]⁺; HPLC purity:98.16%. Retention time 16.22 min.

Example 11: Preparation of(R)-3-(3-((5-(4H-1,2,4-triazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of benzyl(R)-3-((5-carbamoyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution(R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (0.1 g, 0.25 mmol, prepared by the method described in Example 9,Step-1) in N,N-dimethylformamide (1 mL) was added1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.19 g, 0.508 mmol), triethylamine (0.08 g,0.76 mmol) and ammonium chloride (0.07 g, 1.27 mmol). The mixture wasstirred at ambient temperature for 18 hours. The reaction mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to provide benzyl(R)-3-((5-carbamoyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas an off-white solid (0.1 g, crude): MS (ES) m/z 394.1 (M+H).

Step 2: Preparation of benzyl(R,E)-3-((5-(((dimethylamino)methylene)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A stirred solution benzyl(R)-3-((5-carbamoyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.3 g, 0.76 mmol), N,N-dimethylformamide dimethyl acetal (5 mL) andN,N-dimethylformamide (0.3 mL) was heated at 90° C. for 3 hours. Thereaction mixture was concentrated in vacuo to provide benzyl(R,E)-3-((5-(((dimethylamino)methylene)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas an off-white solid (0.25 g, crude): MS (ES) m/z 448.9 (M+H).

Step 3: Preparation of benzyl(R)-3-((5-(4H-1,2,4-triazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A stirred solution of benzyl(R,E)-3-((5-(((dimethylamino)methylene)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.25 g, 0.55 mmol) and hydrazine hydrate (1.2 mL) in acetic acid (2.5mL) was stirred at 90° C. After 3 hours the reaction was cooled toambient temperature, quenched with water and extracted with ethylacetate. The organic layer was washed with water, brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by flash chromatography (5%methanol/dichloromethane) to provide benzyl(R)-3-((5-(4H-1,2,4-triazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas an off-white solid (0.25 g, crude): MS (ES) m/z 417.9 (M+H).

Step 4: Preparation of(R)—N-(piperidin-3-yl)-5-(4H-1,2,4-triazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-aminehydrochloride

(R)—N-(Piperidin-3-yl)-5-(4H-1,2,4-triazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-aminehydrochloride was prepared by the method described in Example 6, Step 5which provided an off-white solid (0.15 g, 98% yield): MS (ES) m/z 284.0(M+H)⁺.

Step 5: Preparation of(R)-3-(3-((5-(4H-1,2,4-triazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

(R)-3-(3-((5-(4H-1,2,4-Triazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrilewas prepared by the method described in Example 9, Step-5 to give anoff-white solid (0.09 g, 7.5% yield): ¹H NMR (400 MHz, DMSO-d₆) 14.13(br s, 1H), 11.49 (br s, 1H), 9.2 (br s, 1H), 8.58-8.61 (br s, 2H), 7.2(s, 1H), 6.66 (s, 1H), 4.35 (br s, 1H), 3.96-4.12 (m, 3H), 3.32-3.69 (m,2H), 2.06 (m, 1H), 1.53-1.76 (m, 3H), 1.21 (s, 1H); MS (ES) m/z 351.2(M+H).

Example 12: Preparation of(1S,3R)-3-((5-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-ol

(1S,3R)-3-Aminocyclopentan-1-ol hydrochloride was prepared by thefollowing method

A solution of tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate (0.5 g,2.48 mmol) in 1,4-dioxane (1 mL) was treated with (4M) hydrochlorideacid in 1,4-dioxane (2.5 mL) and stirred under a nitrogen atmosphere atambient temperature for 12 hours. The reaction mixture was concentratedin vacuo to provide (1S,3R)-3-aminocyclopentan-1-ol hydrochloride as anoff-white solid (0.25 g, crude): MS (ES) m/z 102.1 (M+H).

Step 1: Preparation of5-bromo-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To a solution 5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (5 g, 21.7mmol) in dicholoromethane (40 mL) was added 4-dimethylaminopyridine(0.26 g, 2.17 mmol), p-toulenesufonyl chloride (5.3 g, 28.2 mmol) andtriethylamine (4.3 g, 43.4 mmol) and the mixture stirred at roomtemperature for 12 hours. The reaction was quenched with water andextracted with ethyl acetate. The organic layer was washed with water,brine, dried over anhydrous sodium sulfate, filtered and concentrated invacuo to provide 5-bromo-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine asan off-white solid (7 g, 96% yield): MS (ES) m/z 384.7 (M+H).

Step 2: Preparation of(1S,3R)-3-((5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-ol

To a stirred solution of5-bromo-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.1 g, 0.260 mmol)in N-methyl-2-pyrrolidone (0.6 mL) was added(1S,3R)-3-aminocyclopentan-1-ol hydrochloride (0.03 g, 0.33 mmol) andtriethylamine (0.1 mL) and the mixture was subjected to microwaveirradiation at 150° C. for 2.5 hours. The reaction was cooled to roomtemperature, quenched with water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (50% ethyl acetate/hexane) to provide(1S,3R)-3-((5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-olas a colorless oil (0.15 g, crude): MS (ES) m/z 449.0 (M+H).

Step 3: Preparation of(1S,3R)-3-((5-(pyridin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-ol

A mixture of(1S,3R)-3-((5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-ol(0.3 g, 0.66 mmol), 2-(tributylstannyl)pyridine (0.32 g, 0.86 mmol),lithium chloride (0.002 g, 0.06 mmol), copper iodide (0.01 g, 0.06 mmol)and tetrakis(triphenylphosphine)platinum(0) (0.03 g, 0.033 mmol) inN,N-dimethylformamide (0.5 mL) was degassed with nitrogen for 5 minutes.The reaction mixture was heated in a sealed tube at 120° C. for 2 hours.The reaction mixture was cooled to ambient temperature and filteredthrough celite. The filtrate was diluted with ethyl acetate and washedwith water. The organic phase was washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo. The crude product waspurified by flash chromatography (40% ethyl acetate/hexane) to provide(1S,3R)-3-((5-(pyridin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-olas an off-white solid (0.17 g, 56% yield): MS (ES) m/z 449.3 (M+H).

Step 4: Preparation of(1S,3R)-3-((5-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-ol

To a solution of(1S,3R)-3-((5-(pyridin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-ol(0.17 g, 0.38 mmol) in N-methyl-2-pyrrolidone (1.5 mL) was addedpotassium tert-butoxide (0.09 g, 0.83 mmol) and the mixture was stirredat room temperature for 3 hours. The reaction mixture was quenched withwater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (50% ethyl acetate/hexane) to provide(1S,3R)-3-((5-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-olas an off-white solid (0.02 g, 10% yield): ¹H NMR (400 MHz, DMSO-d₆)11.28 (br s, 1H), 9.99 (d, J=8.0 Hz, 1H), 8.52-8.54 (m, 1H), 8.31 (m,1H), 7.81-7.82 (m, 2H), 7.20-7.22 (m, 1H), 7.09 (s, 1H), 6.60 (s, 1H),4.62 (s, 1H), 4.59-4.61 (m, 1H), 4.18-4.19 (m, 1H), 2.24-2.31 (m, 1H),1.95-2.04 (m, 1H), 1.62-1.83 (m, 2H), 1.48-1.52 (m, 1H), 1.22 (s, 1H);MS (ES) m/z 295.0 (M+H).

Example 13: Preparation of(1S,3R)-3-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-ol

Step 1: Preparation of(1S,3R)-3-((5-(oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-ol

To a stirred solution of2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole(0.2 g, 0.573 mmol as prepared by the method described in Example 5,Step-1) in N-methyl-2-pyrrolidone (0.5 mL) was added(1S,3R)-3-aminocyclopentan-1-ol hydrochloride (0.09 g, 0.86 mmol) andtriethylamine (0.1 mL) and the mixture was subjected to microwaveirradiation at 140° C. for 6 hours. The reaction mixture was cooled toroom temperature, quenched with water and extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (40% ethyl acetate/hexane) to provide(1S,3R)-3-((5-(oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-olas a colorless oil (0.19 g, 80% yield): MS (ES) m/z 415.0 (M+H).

Step 2: Preparation of(1S,3R)-3-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-ol

A solution of(1S,3R)-3-((5-(oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-ol(0.19 g, 0.46 mmol) in dichloromethane:trifluoroacetic acid (2 ml:2 mL)was stirred at ambient temperature for 3 hours. The volatiles wereremoved in vacuo and the residue was dissolved dioxane:aqueous ammonia(5 mL:5 mL) and the mixture was stirred at ambient temperature for 12hours. The reaction was quenched with water and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to provide(1S,3R)-3-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentan-1-olas an off-white solid (0.06 g, 50% yield): ¹H NMR (400 MHz, DMSO-d₆)11.52 (br s, 1H), 9.13 (d, J=8.0 Hz, 1H), 8.50 (s, 1H), 8.08 (s, 1H),7.36 (s, 1H), 7.16 (s, 1H), 6.65 (s, 1H), 4.65-4.66 (m, 1H), 4.52 (m,1H), 4.18-4.19 (m, 1H), 2.31-2.48 (m, 1H), 2.09-2.18 (m, 1H), 1.66-1.81(m, 3H), 1.48-1.53 (m, 1H); MS (ES) m/z 285.3 (M+H).

Example 14: Preparation of(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide

Step 1: Preparation of ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylate

To a stirred solution of tert-butyl(R)-3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.8 g, 1.522 mmol, as prepared by the method described in Scheme 1,Step 5) in 1,4-dioxane (8 mL) was added ethyl oxazole-4-carboxylate(0.03 g, 1.83 mmol) and cesium carbonate (0.99 g, 3.044 mmol) at roomtemperature and the solution was degassed with nitrogen for 15 minutes.Palladium acetate (0.017 g, 0.0761 mmol) and CyJohnphos (0.053 g, 0.1522mmol) were added and the resulting mixture was heated in a sealed tubeto 110° C. for 16 hours. The reaction was cooled to ambient temperature,filtered through celite and the filtrate was concentrated in vacuo. Thecrude was purified by column chromatography (ethyl acetate/hexane) toprovide ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylateas a yellow solid (0.35 g, 39% yield): MS (ES) m/z 585.9 (M+H).

Step 2: Preparation of tert-butyl(R)-3-((5-(4-carbamoyloxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A solution of ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylate(0.35 g, 0.597 mmol) and 23% aqueous ammonia (16 mL) in methanol (5 mL)was stirred in a sealed tube for 40 hours. The reaction mixture wasconcentrated in vacuo and the aqueous portion was extracted withdichloromethane. The organic extract was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudewas purified by column chromatography (ethyl acetate/hexane) to providetert-butyl(R)-3-((5-(4-carbamoyloxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a yellow solid (0.12 g, 36% yield): MS (ES) m/z 556.9 (M+H).

Step 3: Preparation of(R)-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide

(R)-2-(4-(Piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamidewas prepared by the method described in Example 1, Step-7 to give titlecompound (0.1 g crude): MS (ES) m/z 327.0 (M+H).

Step 4: Preparation of(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide

(R)-2-(4-((1-(2-Cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamidewas prepared by the method described in Example 9, Step-5 to give a palebrown solid (0.01 g, 13% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (d,J=12.0 Hz, 1H), 8.71 (d, J=8.4 Hz, 1H), 8.52-8.53 (m, 2H), 7.56-7.67 (m,2H), 7.24 (s, 1H), 6.72 (s, 1H), 4.14-4.29 (m, 2H), 4.07 (s, 1H),3.77-3.94 (m, 2H), 3.52 (d, J=14.4 Hz, 1H), 3.00-3.25 (m, 1H), 2.08 (bs,1H), 1.85 (bs, 2H), 1.50-1.70 (m, 1H); MS (ES) m/z 394.1 (M+H).

Analytical Conditions:

Column: X Bridge C18 (250 mm×4.6 mm×5 mic)

Mobile phase(A): 0.1% Ammonia in water

Mobile phase(B): ACN

Flow rate: 1.0 mL/min

Composition of B: 0/10, 12/60, 25/90, 27/10, 30/10

Example 15: Preparation of(R)-3-(3-((5-(4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

To a solution of(R)-3-(3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile(0.2 g, 0.55 mmol, prepared by the method as described in Scheme 23,Step-4) in N,N-dimethylformamide (5 mL) was added lithium chloride(0.048 g, 1.1 mmol), 4-methyl-2-(tributylstannyl)pyridine (0.25 g, 0.66mmol), copper iodide (0.011 g, 0.05 mmol), andtetrakis(triphenyl-phosphine)palladium (0) (0.03 g, 0.02 mmol). Themixture was stirred in a sealed tube at 120° C. for 3 hours under anitrogen atmosphere. The reaction was cooled to ambient temperature,diluted with ethyl acetate and water. The organic layer was separated,washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by reverse phasechromatography to provide(R)-3-(3-((5-(4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.02 g, 8% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.42-11.37 (m, 1H), 10.13-10.02 (m, 1H), 8.42-8.32 (m, 2H), 7.75-7.72(m, 1H), 7.15-7.08 (m, 2H), 6.61 (s, 1H), 4.38 (m, 1H), 4.12-3.94 (m,3H), 3.73-3.55 (m, 3H), 2.31 (s, 3H), 1.97 (s, 1H), 1.69-1.52 (s, 3H);MS (ES) m/z 375.1 (M+H). HPLC purity: 99.38%.

Analytical Conditions:

Column: Inertsil ODS 3V (150 mm×4.6 mm×5 mic)

Mobile phase(A): 0.1% Ammonia in water

Mobile phase(B): ACN

Flow rate: 1.0 mL/min

Example 16: Preparation of(R)-3-oxo-3-(3-((5-(thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile

A solution of (R)-3-(3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (0.2 g,0.55 mmol, prepared by the method as described in Scheme 23, Step 4),5-(tributylstannyl)thiazole (0.24 g, 0.66 mmol) andbis(triphenylphosphine)palladium(II) dichloride (0.09 g, 0.027 mmol) inacetonitrile (5 mL) was heated in a sealed tube to 80° C. for 15 hours.The reaction mixture was cooled to ambient temperature and quenched withwater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (5% methanol/dichloromethane) to provide(R)-3-oxo-3-(3-((5-(thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrileas an off-white solid (0.04 g, 22% yield): ¹H NMR (400 MHz, DMSO-d₆, at70° C.) δ 11.29 (s, 1H), 9.10 (s, 1H), 7.86 (s, 1H), 7.79 (s, 1H), 7.20(s, 1H), 6.58 (s, 1H), 5.04 (s, 1H), 4.13 (br s, 1H), 3.82-3.99 (m, 3H),3.53-3.65 (m, 1H), 3.35-3.44 (m, 1H), 1.94 (br s, 1H), 1.40-1.65 (m,3H), 1.29-1.30 (m, 1H); MS (ES) m/z 367.2 (M+1).

Example 17: Preparation of(R)-3-(3-((5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A solution of (R)-3-(3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (0.3 g,0.82 mmol, prepared by the method as described in Scheme 23, Step 4),1-methyl-2-(tributylstannyl)-1H-imidazole (0.46 g, 1.24 mmol) andtetrakis(triphenylphosphine)palladium (0) (0.09 g, 0.08 mmol) in1,4-dioxane (4 mL) was subjected to microwave irradiation at 140° C. for2 hours. The reaction mixture was cooled to ambient temperature, dilutedwith ethyl acetate. The organic layer was washed with water, brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The crude material was purified by flash chromatography (5%methanol/dichloromethane) to provide(R)-3-(3-((5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.04 g, 15% yield): ¹H NMR (400 MHz, DMSO-d₆, at70° C.) δ 11.41 (s, 1H), 7.72-7.74 (m, 1H), 7.63-7.64 (m, 1H), 7.21 (s,1H), 6.88 (s, 1H), 6.59-6.64 (m, 1H), 4.85-4.99 (m, 2H), 3.79-4.20 (m,5H), 2.68-3.07 (m, 3H), 1.91 (bs, 2H), 1.49-1.56 (m, 3H); MS (ES) m/z364.1 (M+1).

Example 18: Preparation of(R)-3-(3-((5-(1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A mixture of (R)-3-(3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (0.2 g,0.55 mmol, prepared by the method as described in Scheme 23, Step 4),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.16 g,0.83 mmol), sodium carbonate (0.17 g, 1.65 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.03 mmol) in1,4-dioxane (4 mL)/water (1 mL) was subjected to microwave irradiationat 100° C. for 3 hours. The reaction mixture was cooled to ambienttemperature and diluted with ethyl acetate. The organic layer was washedwith water, brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (5% methanol/dichloromethane) to provide(R)-3-(3-((5-(1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.045 g, 15% yield): ¹H NMR (400 MHz, DMSO-d₆, at70° C.) δ 12.67 (s, 1H), 11.11 (s, 1H), 8.63 (s, 1H), 8.31 (s, 1H), 7.75(s, 1H), 7.12 (s, 1H), 6.70 (s, 1H), 6.60 (s, 1H), 4.41 (br s, 1H),3.81-4.09 (m, 3H), 3.51 (br s, 1H), 3.22 (s, 1H), 2.99 (s, 1H), 2.11 (brs, 1H), 1.61-1.81 (m, 3H); MS (ES) m/z 350.3 (M+1).

Example 19: Preparation of(R)-3-(3-((5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of tert-butyl(R)-5-bromo-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

To a solution of(R)-5-bromo-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (crude)(5.0 g, 17.0 mmol, prepared by the method as described in Scheme 23,Step 3) in dichloromethane (70 mL) was added di-tert-butyl dicarbonate(3.9 mL, 17.0 mmol), triethylamine (4.7 mL, 34 mmol) and4-dimethylaminopyridine (0.02 g, 0.17 mmol) and the mixture was stirredat ambient temperature for 16 hours. The reaction mixture was dilutedwith dichloromethane and washed with water, brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography (30% ethyl acetate/hexane) toprovide tert-butyl(R)-5-bromo-4-((1-(tert-butoxycarbonyl)-piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-1-carboxylateas an off-white solid (1.2 g, 14% yield): MS (ES) m/z 496.8 (M+2).

Step 2: Preparation of tert-butyl(R)-3-((5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A suspension of tert-butyl(R)-5-bromo-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(1.5 g, 3.02 mmol), zinc cyanide (0.53 g, 4.54 mmol) andtetrakis(triphenyl-phosphine)palladium(0) (0.87 g, 0.75 mmol) indimethylacetamide (15 mL) was heated in a sealed tube at 130° C. for 16hours under argon atmosphere. The reaction mixture was cooled to ambienttemperature and diluted with ethyl acetate. The organic layer was washedwith water, brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (30% ethyl acetate/hexane) to provide tert-butyl(R)-3-((5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas an off-white solid (0.7 g, crude): MS (ES) m/z 342.2 (M+H).

Step 3: Preparation of tert-butyl(R,Z)-3-((5-(N-hydroxycarbamimidoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A suspension of tert-butyl(R)-3-((5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.2 g, 0.58 mmol), hydroxylamine hydrochloride (0.06 g, 0.88 mmol) andtriethylamine (0.16 mL, 1.17 mmol) in ethanol (5 mL) was heated under anargon atmosphere at 90° C. for 15 hours. The reaction mixture was cooledto ambient temperature and concentrated in vacuo to remove volatiles.The residue was dissolved in dichloromethane and washed with water,brine solution, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to provide tert-butyl(R,Z)-3-((5-(N-hydroxycarbamimidoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a viscous solid (0.21 g, 95% yield): MS (ES) m/z 375.2 (M+1).

Step 4: Preparation of tert-butyl(R)-3-((5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A solution of tert-butyl(R,Z)-3-((5-(N-hydroxycarbamimidoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate (0.1 g, 0.27 mmol) in acetic anhydride (2 mL)was heated at 140° C. for 45 minutes. The reaction mixture was cooled toambient temperature, neutralized using aqueous ammonia and extractedwith dichloromethane (30 ml). The organic layer was washed with water,brine, dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The crude mass was dissolved in methanol (4 mL) and 3M aqueoussodium hydroxide solution (2 mL) was added and then the solution stirredat ambient temperature for 2 hours. The reaction mixture wasconcentrated in vacuo to remove volatiles; the residue was dissolved indichloromethane, washed with water, brine, dried over anhydrous sodiumsulfate. The solution was filtered and concentrated in vacuo to providetert-butyl(R)-3-((5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas an off-white solid (0.12 g, crude): MS (ES) m/z 399.0 (M+H).

Step 5: Preparation of(R)-5-(5-methyl-1,2,4-oxadiazol-3-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of tert-butyl(R)-3-((5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.12 g, 0.3 mmol) in dichloromethane:trifluoroacetic acid (3 mL:0.5 mL)was stirred for 3 hours at ambient temperature. The reaction mixture wasconcentrated in vacuo to remove volatiles, neutralized by using aqueousammonia and extracted with dichloromethane (30 mL). The organic layerwas washed with water, brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to provide(R)-5-(5-methyl-1,2,4-oxadiazol-3-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas an off-white solid (0.1 g, crude): MS (ES) m/z 299.0 (M+1).

Step 5: Preparation of(R)-3-(3-((5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

(R)-3-(3-((5-(5-Methyl-1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrilewas prepared by the method described in Example 1, Step 8 to give anoff-white solid (0.01 g, 9% yield): ¹H NMR (400 MHz, DMSO-d₆, at 60° C.)δ 11.64 (s, 1H), 8.67 (s, 1H), 7.49-7.57 (m, 1H), 7.25 (s, 1H), 6.70 (s,1H), 4.21 (br s, 1H), 4.03-4.12 (m, 2H), 3.66-3.84 (m, 1H), 3.42-3.53(m, 2H), 2.65 (s, 3H), 2.06 (br s, 2H), 1.65-1.73 (m, 3H); MS (ES) m/z366.1 (M+H).

Examples 20-25: Preparation of 5-aryl substituted pyrrolopyridines

Step 1: Preparation of5-bromo-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To a solution of 5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (15 g, 65.0mmol) in dichloromethane (200 mL) was added triethylamine (18.2 mL, 130mmol), p-toluenesulfonyl chloride (18.5 g, 97 mmol) and4-dimethylaminopyridine (0.79 g, 6.0 mmol) at 0° C. The solution wasstirred at ambient temperature for 16 hours. The reaction mixture wasdiluted with dichloromethane, washed with water, brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudeproduct was triturated with n-pentane and dried to provide5-bromo-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine as an off-white solid(23.0 g, 92% yield): MS (ES) m/z 386.7 (M+2).

Step 2: Preparation of(R)—N-(1-benzylpiperidin-3-yl)-5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine

A mixture of 5-bromo-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (10.0 g,25.0 mmol) and (R)-1-benzylpiperidin-3-amine (9.88 g, 52 mmol) washeated in a sealed tube to 180° C. for 3 hours. The reaction mixture wascooled to ambient temperature and the crude material was purified byflash chromatography (30% ethyl acetate/hexane) to provide(R)—N-(1-benzylpiperidin-3-yl)-5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amineas a pale yellow sticky solid (9.1 g, 66% yield): MS (ES) m/z 541.1(M+2).

Step 3: Preparation of(R)-5-bromo-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

To a solution of(R)—N-(1-benzylpiperidin-3-yl)-5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine(10.0 g, 18.5 mmol) in 1,4-dioxane (200 mL) was added ethylchloroformate (2.1 mL, 22.6 mmol) and the resulting mixture was heatedto 100° C. After 16 hours the reaction mixture was cooled to ambienttemperature and was concentrated in vacuo. The crude intermediate wasdissolved in methanol:water (150 mL:70 mL) and potassium hydroxide(20.75 g, 370 mmol) was added and the mixture heated at 90° C. for 16hours. The reaction mixture was cooled to ambient temperature andconcentrated in vacuo to remove volatiles. The residue was dissolved indichloromethane and washed with water, brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to provide(R)-5-bromo-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine as abrown oil (8.4 g, crude): MS (ES) m/z 297.0 (M+2).

Step-4: Preparation of(R)-3-(3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

To a solution of(R)-5-bromo-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (8.4 g,28.4 mmol) in dichloromethane (150 mL) was added cyanoacetic acid (4.84g, 56.9 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.hydrochloride (10.94 g, 56.9 mmol), hydroxybenzotriazole(7.68 g, 56.9 mmol) and N,N-disopropylethylamine (14.7 mL, 85.4 mmol).The reaction mixture was stirred for 16 hours at ambient temperature.The reaction mixture was diluted with dichloromethane (150 mL) andwashed with water, brine solution, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude material was purified byflash chromatography (5% methanol/dichloromethane) to provide(R)-3-(3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (2.8 g, 27% yield): ¹H NMR (400 MHz, DMSO-d₆, at60° C.) δ 11.37 (b, 1H), 7.96 (s, 1H), 7.20 (s, 1H), 6.57 (s, 1H), 5.19(d, J=8.8 Hz, 1H), 4.20 (br s, 1H), 3.80-4.10 (m, 4H), 3.52-3.54 (m,1H), 3.01 (br s, 1H), 2.02 (br s, 1H), 1.51-1.75 (m, 3H); MS (ES) m/z364.2 (M+2).

General procedure for cross coupling reaction

A mixture of(R)-3-(3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile(1.0 equiv), Aryl/Heteroaryl(tributyl or stannyl) (1.2 eq), lithiumchloride (2.0 eq), copper iodide (0.1 eq) andtetrakis(triphenylphosphine)palladium (0) in N,N-dimethylformamide (5mL) was heated to 120° C. for 3 hours under argon atmosphere. Thereaction mixture was cooled to ambient temperature and diluted withethyl acetate. The ethyl acetate layer washed with water, brine, driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Thecrude material was purified by flash chromatography (5%methanol/dichloromethane) to provide the desired products as indicatedin Table 2.

TABLE 2 The following compounds were prepared by the method describedabove: Example # Structure IUPAC Name Analytical Data 20

(R)-3-(3-(5-(6- methylpyridin-2- yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)piperidin- 1-yl)-3- oxopropanenitrile ¹H NMR (400 MHz, DMSO- d₆at 70° C.) δ 11.21 (br s, 1H), 9.96-10.07 (m, 2H), 8.36 (s, 1H), 7.72(m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.09-7.14 (m, 1H), 6.63 (s, 1H),4.28-4.43 (m, 1H), 3.90-4.15 (m, 1H), 3.62-3.88 (m, 1H), 3.42-3.58 (m,2H), 2.95-3.08 (m, 1H), 2.52 (s, 3H), 2.10-2.18 (m, 2H), 1.55-1.82 (m,3H); MS (ES) m/z 375.1 (M + H). 21

(R)-3-oxo-3-(3-((5- (pyridin-2-yl)-1H- pyrrolo[2,3- b]pyridin-4-yl)amino)piperidin- 1-yl)propanenitrile ¹H NMR (400 MHz, DMSO- d₆ at 70°C.) δ 11.2 (bs, 1H), 9.82-9.98 (m, 1H), 8.55 (bs, 1H), 8.37 (bs, 1H),7.85 (s, 2H), 7.23 (s, 1H), 7.14 (s, 1H), 6.62 (s, 1H), 4.17-4.38 (m,1H), 3.97 (bs, 3H), 3.60- 3.72 (m, 1H), 3.20-3.69 (m, 2H), 2.00 (bs,2H), 1.62-1.71 (m, 2H); MS (ES) m/z 361.3 (M+). 22

(R)-3-(3-(5-(5- methylpyridin-2- yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)piperidin- 1-yl)-3- oxopropanenitrile ¹H NMR (400 MHz, DMSO- d₆at 70° C.) 11.24 (s, 1H), 9.90 (s, 1H), 8.38-8.39 (m, 2H), 7.68-7.75 (m,2H), 7.14 (s, 1H), 6.62 (s, 1H), 4.32- 4.42 (m, 1H), 4.12-4.25 (m, 1H),3.90-3.98 (m, 2H), 3.44- 3.65 (m, 2H), 2.32 (s, 3H), 1.99-2.07 (m, 2H),1.58-1.72 (m, 3H); MS (ES) m/z 375.3 (M + H). 23

(R)-3-oxo-3-(3-((5- (pyrimidin-2-yl)- 1H-pyrrolo[2,3- b]pyridin-4-yl)amino)piperidin- 1-yl)propanenitrile ¹H NMR (400 MHz, DMSO- d₆ at 70°C.) 11.23 (s, 1H), 10.27-10.29 (m, 1H), 9.18 (s, 1H), 8.77 (d, J = 4.8Hz, 1H), 7.25 (s, 1H), 7.13 (s, 1H), 6.64-6.65 (d, J = 1.6 Hz, 1H),4.38-4.51 (m, 1H), 4.10-4.36 (m, 1H), 3.91-4.10 (m, 2H), 3.58-3.80 (m,1H), 3.47-3.57 (m, 1H), 3.36-3.41 (m, 1H), 2.01-2.09 (m, 1H), 1.71-1.89(m, 1H), 1.58 (s, 2H), 1.33 (s, 1H); MS (ES) m/z 362.3 (M + H). 24

(R)-3-oxo-3-(3-((5- (pyrimidin-4-yl)- 1H-pyrrolo[2,3- b]pyridin-4-yl)amino)piperidin- 1-yl)propanenitrile ¹H NMR (400 MHz, DMSO- d₆ at 70°C.) 11.42 (s, 1H), 10.34 (s, 1H), 9.05 (s, 1H), 8.65-8.57 (m, 2H), 8.00(s, 1H), 7.17 (s, 1H), 6.66 (s, 1H), 4.24-4.43 (m, 1H), 3.9- 4.02 (m,1H), 3.52-3.71 (m, 2H), 3.40 (s, 2H), 2.04 (s, 1H), 1.68-1.75 (m, 3H);MS (ES) m/z 362.0 (M + H).

Example 25: Preparation of(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile

Scheme 24: Preparation of(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile

A suspension of(R)-3-(3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile(0.2 g, 0.55 mmol as prepared by the method described in Scheme 23, Step4), zinc cyanide (0.01 mg, 0.83 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) indimethylformamide (5 mL) was heated in a sealed tube at 130° C. for 16hours under argon atmosphere. The reaction mixture was cooled to roomtemperature and diluted with ethyl acetate. The organic layer was washedwith water, brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude product was purified by reverse phasechromatography to provide(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrileas an off-white solid (0.04 g, 26% yield): ¹H NMR (400 MHz, DMSO-d₆ at70° C.) 11.67 (s, 1H), 8.07 (s, 1H), 7.23 (s, 1H), 6.71 (s, 1H),6.21-6.66 (m, 1H), 4.05-4.29 (m, 2H), 3.99 (s, 2H), 3.53-3.91 (m, 1H),2.85-3.02 (m, 1H), 2.03-2.10 (m, 2H), 1.68-1.78 (m, 3H); MS (ES) m/z309.2 (M+H). HPLC purity: 99.58%

Prep. HPLC Conditions:

Column: Kinetex C18 (100 mm×4.6 mm×2.6 μm)

Mobile phase A: 0.1% TFA in Water

Mobile phase B: ACN

Flow rate: 0.75 mL/min

Example 26: Preparation of(R)-3-(3-((5-(3-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of3-((3R)-3-((5-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A mixture of(R)-3-(3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile(0.5 g, 1.38 mmol, as prepared by the method described in Scheme 23,Step 4),3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.6 g, 2.07 mmol), cesium carbonate (1.35 g, 4.14 mmol) andtetrakis(triphenylphosphine)palladium (0) (0.08 g, 0.07 mmol) in1,4-dioxane:water (4 mL:1 mL) was heated in a sealed tube at 100° C. for5 hours under an argon atmosphere. The reaction mixture was cooled toambient temperature and diluted with ethyl acetate and water. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (80% ethyl acetate/hexane) to provide3-((3R)-3-((5-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas a brown solid (0.2 g, 32% yield): MS (ES) m/z 448 (M+H).

Step 2: Preparation of(R)-3-(3-((5-(3-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A stirred solution of3-((3R)-3-((5-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile(0.2 g, 0.44 mmol) and p-toluenesulfonic acid (0.15 g, 0.89 mmol) inmethanol (5 mL) was heated at 60° C. for 12 hours. The reaction mixturewas cooled to room temperature and concentrated in vacuo. The crudematerial was purified by reverse phase chromatograpy to provide(R)-3-(3-((5-(3-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.01 g, 6% yield): ¹H NMR (400 MHz, DMSO-d₆) δ12.52 (s, 1H), 11.35 (s, 1H), 8.24-8.27 (m, 1H), 7.44-7.46 (m, 1H),7.08-7.16 (m, 2H), 6.47-6.50 (m, 1H), 4.31 (s, 1H), 3.89-4.11 (m, 2H),3.49-3.69 (m, 2H), 3.20 (s, 3H), 2.94 (s, 2H), 2.27 (m, 3H), 2.05-2.10(m, 1H); MS (ES) m/z 364.1 (M+).

Analytical conditions: Flow rate: 0.3 mL/min

Column: BEH C18 (100 mm×2.1 mm×1.7 μm)

Mobile Phase (A): 0.1% Formic acid in water

Mobile Phase (B): ACN

Example 27: Preparation of(R)-3-(3-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile

Step 1: Preparation of2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole

A mixture of5-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(2.00 g, 5.54 mmol), oxazole (0.68 g, 9.97 mmol), potassiumtert-butoxide (1.24 g, 11.1 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.19 g, 0.27 mmol) in 1,4-dioxane(20 mL) was heated in a sealed tube at 110° C. under nitrogen. After 5hours the reaction was cooled to ambient temperature, diluted with waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over sodium sulfate, filtered and concentrated in vacuo.The crude material was purified by flash chromatography (10% ethylacetate/hexane) to provide2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazoleas an off-white solid (0.43 g, 22% yield): MS (ES) m/z 349.9 (M+H).

Step 2: Preparation of tert-butyl(R)-3-((5-(oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A stirred solution of2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole(0.43 g, 1.28 mmol), triethylamine (0.03 mL, 0.24 mmol) and tert-butyl(R)-3-aminopiperidine-1-carboxylate (0.46 g, 2.32 mmol) inN-methylpyrrolidone (4 mL) was subjected to microwave irradiation at130° C. for 5 hours. The reaction was cooled to ambient temperature,diluted with water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified using flashchromatography (50% ethyl acetate/hexane) to provide tert-butyl(R)-3-((5-(oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas an off-white solid (0.35 g, 53% yield): MS (ES) m/z 514.0 (M+H).

Step 3: Preparation of(R)-5-(oxazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of tert-butyl(R)-3-((5-(oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.12 g, 0.23 mmol) in dichloromethane:trifluoroacetic acid (3 mL:3 mL)was stirred at ambient temperature for 3 hours. The reaction mixture wasconcentrated in vacuo, the residue was dissolved in 1,4-dioxane:aqueousammonia (3 mL:3 mL, 23% in water) and the mixture was stirred at ambienttemperature for 16 hours. The reaction mixture was concentrated in vacuoto provide(R)-5-(oxazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas an off-white solid (0.05 g, crude): MS (ES) m/z 284.2 (M+H).

Step 4: Preparation of(R)-3-(3-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile

To a stirred solution of(R)-5-(oxazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.05 g, 0.17 mmol) in ethanol (3 mL), was added acrylonitrile (0.09 g,1.7 mmol) followed by trimethylamine (0.05 mL, 0.34 mmol) and thesolution was stirred at 80° C. for 3 hours. The reaction was cooled toambient temperature and concentrated in vacuo. The crude material waspurified using flash chromatography (5% methanol/dichloromethane) toprovide(R)-3-(3-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrileas an off-white solid (0.03 g, 45% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.53 (br s, 1H), 9.17 (br s, 1H), 8.50 (s, 1H), 8.06 (s, 1H), 7.36 (s,1H), 7.17 (s, 1H), 6.56 (s, 1H), 4.14-4.27 (m, 1H), 2.85-2.98 (m, 1H),2.55-2.66 (m, 2H), 2.83-2.97 (m, 2H), 1.52-1.69 (m, 2H), 1.42-1.60 (m,3H), 1.21 (s, 2H); MS (ES) m/z 337.2 (M+H).

Example 28: Preparation of3-((2S,5R)-2-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of benzyl(2S,5R)-2-methyl-5-((5-(oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole(0.2 g, 0.57 mmol) (obtained from Example 27, Step 1) and benzyl(2S,5R)-5-amino-2-methylpiperidine-1-carboxylate (0.21 g, 0.85 mmol) in1,4-dioxane (5 mL), was added potassium tert-butoxide (0.16 g, 1.71mmol), palladium(II) acetate (0.02 g, 0.08 mmol) and(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.05 g, 0.08 mmol)and the resulting mixture was subjected to MW irradiation at 100° C. for45 minutes. The reaction was cooled to ambient temperature, diluted withwater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate, filtered and concentrated invacuo. The crude material was purified by flash chromatography (40%ethyl acetate/hexane) to provide benzyl(2S,5R)-2-methyl-5-((5-(oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a colorless gummy liquid (0.12 g, 37% yield); MS (ES) m/z 561.9(M+H).

Step 2: Preparation ofN-((3R,6S)-6-methylpiperidin-3-yl)-5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of benzyl(2S,5R)-2-methyl-5-((5-(oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(2.0 g, 0.35 mmol) in trifluoroacetic acid (2.0 mL) was stirred at 100°C. for 1 hour. The reaction was cooled to ambient temperature and themixture was concentrated in vacuo, the residue was dissolved in1,4-dioxane:aqueous ammonia (2 mL:2 mL) and was stirred at ambienttemperature for 16 hours. The reaction mixture was concentrated in vacuoto provideN-((3R,6S)-6-methylpiperidin-3-yl)-5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a pale yellow gummy liquid (0.1 g, crude): MS (ES) m/z 298.0 (M+H).

Step 3: Preparation of3-((2S,5R)-2-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) piperidin-1-yl)-3-oxopropanenitrile

To a solution of cyanoacetic acid (0.03 g, 0.4 mmol) and1-hydroxybenzotriazole (0.055 g, 0.4 mmol) in dichloromethane (5 mL),was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(0.1 g, 0.51 mmol) and the mixture stirred at ambient temperature for 5minutes. At this timeN-((3R,6S)-6-methylpiperidin-3-yl)-5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.1 g, 0.34 mmol) was added followed by N,N-diisopropylethylamine (0.18mL, 1.02 mmol) and then the resulting mixture was stirred at ambienttemperature for 18 hours. The reaction was quenched with water andextracted with dichloromethane. The organic layer was washed with water,brine, dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The crude material was purified by flash chromatography (5%methanol/dichloromethane) and further purified by reverse phasechromatograpy to provide3-((2S,5R)-2-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.04 g, 33% yield): ¹H NMR (400 MHz, DMSO-d₆, VTat 70° C.) δ 11.43 (br s, 1H), 8.92 (d, J=7.6 Hz, 1H), 8.55 (s, 1H),8.05 (s, 1H), 7.36 (s, 1H), 7.20 (s, 1H), 6.68 (s, 1H), 3.93-4.02 (m,3H), 3.56 (s, 2H), 1.80-2.12 (m, 2H), 1.60-1.79 (m, 2H), 1.24 (s, 4H);MS (ES) m/z 365.1 (M+H).

Analytical Conditions: Flow rate: 0.3 mL/min

Column: BEH C18 (50 mm×2.1 mm×1.7 μm)

Mobile Phase (A): 0.1% Formic acid in water

Mobile Phase (B): MeCN

Example 29: Preparation of2-(4-(((1S,3R)-3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide

Step 1: Preparation of ethyl2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylate

To a stirred solution of5-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(0.8 g, 2.22 mmol) and ethyl oxazole-4-carboxylate (0.37 g, 2.66 mmol)in 1,4-dioxane (30 mL), was added palladium acetate (0.024 g, 0.11mmol), CyJohnphos (0.08 g, 0.22 mmol) and cesium carbonate (1.44 g, 4.44mmol) and the mixture was heated in a sealed tube at 110° C. for 16hours. The reaction was cooled to room temperature, filtered throughcelite and the filtrate was concentrated in vacuo. The crude waspurified using flash chromatography (30% ethyl acetate/hexane) toprovide ethyl2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylateas a brown liquid (0.41 g, 44% yield): MS (ES) m/z 421.9 (M+H).

Step 2: Preparation of ethyl2-(4-(((1S,3R)-3-hydroxycyclopentyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylate

To a stirred solution of ethyl2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylate(0.4 g, 0.95 mmol) in N-methylpyrrolidone (5 mL) was added(1R,3S)-3-aminocyclopentan-1-ol hydrochloride (0.13 g, 0.95 mmol)followed by trimethylamine (0.17 mL, 1.23 mmol). The resulting mixturewas subjected to microwave irradiation at 150° C. for 45 minutes. Thereaction was cooled to ambient temperature, diluted with water andextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by flash chromatography (50% ethyl acetate/hexane)to provide ethyl2-(4-(((1S,3R)-3-hydroxycyclopentyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylateas a colorless thick liquid (0.31 g, 67% yield): MS (ES) m/z 486.9(M+H).

Step 3: Preparation of2-(4-(((1S,3R)-3-hydroxycyclopentyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide

A stirred solution of ethyl2-(4-(((1S,3R)-3-hydroxycyclopentyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylate(0.30 g, 0.62 mmol), methanol (5 mL) and aqueous ammonia (5 mL, 23% inwater) was stirred at ambient temperature for 20 hours. The reactionmixture was concentrated in vacuo to provide2-(4-(((1S,3R)-3-hydroxycyclopentyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamideas a white solid (0.28 g, 99% yield): MS (ES) m/z 457.9 (M+H).

Step 4: Preparation of2-(4-(((1S,3R)-3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide

A solution of2-(4-(((1S,3R)-3-hydroxycyclopentyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide(0.25 g, 0.55 mmol) in dichloromethane:trifluoroacetic acid (3 mL:3 mL)was stirred at ambient temperature for 3 hours. The mixture wasconcentrated in vacuo, the residue was dissolved in 1,4-dioxane:aqueousammonia (3 mL:5 mL, 23% in water) and the solution was stirred atambient temperature for 16 hours. The reaction mixture was concentratedin vacuo and the crude material was purified using flash chromatography(5% methanol/dichloromethane) to provide2-(4-(((1S,3R)-3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamideas an off-white solid (0.05 g, 35% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.56 (br s, 1H), 9.35 (d, J=8.4 Hz, 1H), 8.48 (d, J=8.4 Hz, 1H), 7.58(s, 1H), 7.17 (s, 1H), 6.71 (s, 1H), 5.13 (s, 1H), 4.63 (s, 1H), 4.35(s, 1H), 2.05-2.19 (m, 2H), 1.82-2.00 (m, 2H), 1.75-1.80 (m, 1H),1.15-1.30 (m, 3H); MS (ES) m/z 328.1 (M+H).

Intermediate

Preparation of (1S,3R)-3-aminocyclopentan-1-ol hydrochloride

To a solution of tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate (0.5g, 2.48 mmol) in 1,4-dioxane (1 mL) was added 4N hydrochloric acid in1,4-dioxane (2.5 mL) and stirred at ambient temperature for 12 hours.The reaction mixture was concentrated in vacuo to provide ethyl(S)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylatehydrochloride as an off-white solid (0.25 g, crude): MS (ES) m/z 102.1(M+H).

Example 30: Preparation of2-(4-(((3R,6S)-1-(2-cyanoacetyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide

Step 1: Preparation of ethyl2-(4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylate

In a 10 mL vial, a solution of ethyl2-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-oxazole-4-carboxylate(2.0 g, 4.74 mmol) (obtained from Example 29, Step 1), benzyl(2S,5R)-5-amino-2-methylpiperidine-1-carboxylate (2.35 g, 9.48 mmol) anddiisopropylethylamine (1.29 mL, 14.2 mmol) in N-methylpyrrolidone (15mL) was heated at 130° C. for 16 h. The reaction mixture was cooled toambient temperature, diluted with ethyl acetate, washed with water,brine, dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The crude material was purified using flash chromatography (30%ethyl acetate/hexane) to provide benzyl(2S,5R)-5-({5-[4-(ethoxycarbonyl)-1,3-oxazol-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)-2-methylpiperidine-1-carboxylateas a pale yellow gummy liquid (0.71 g, 24% yield): MS (ES) m/z 634.3(M+H).

Step 2: Preparation of2-(4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylicacid

A solution of benzyl(2S,5R)-5-({5-[4-(ethoxycarbonyl)-1,3-oxazol-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)-2-methylpiperidine-1-carboxylate(0.60 g, 0.95 mmol), methanol (20 mL), and a 2M aqueous solution ofsodium hydroxide (0.2 g, 4.73 mmol) was stirred at ambient temperaturefor 5 hours. Volatiles were removed in vacuo, the residue was dissolvedin water and acidified with 1N hydrochloric acid and adjusted pH-3. Theaqueous layer was extracted with dichloromethane, washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuoto provide2-(4-{[(3R,6S)-1-[(benzyloxy)carbonyl]-6-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-oxazole-4-carboxylicacid as a colorless thick liquid (0.51 g, 89% yield): MS (ES) m/z 606.3(M+H).

Step 3: Preparation of benzyl(2S,5R)-2-methyl-5-({5-[4-(methylcarbamoyl)-1,3-oxazol-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)piperidine-1-carboxylate

To a stirred solution of2-(4-{[(3R,6S)-1-[(benzyloxy)carbonyl]-6-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-oxazole-4-carboxylicacid (0.5 g, 0.82 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.48 g, 1.24 mmol) in N,N-dimethylformamide(8 mL) at ambient temperature was added methylamine hydrochloride (0.13g, 4.13 mmol) followed by triethylamine (0.6 mL, 4.13 mmol) and themixture stirred at ambient temperature for 10 hours. The reactionmixture was diluted with ethyl acetate, washed with water and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (30% ethyl acetate/hexane) to provide benzyl(2S,5R)-2-methyl-5-({5-[4-(methylcarbamoyl)-1,3-oxazol-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)piperidine-1-carboxylateas a pale yellow sticky solid (0.32 g, 63% yield): MS (ES) m/z 619.3(M+H).

Step 4: Preparation ofN-methyl-2-(4-{[(3R,6S)-6-methylpiperidin-3-yl]amino}-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-oxazole-4-carboxamide

A solution of benzyl(2S,5R)-2-methyl-5-({5-[4-(methylcarbamoyl)-1,3-oxazol-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)piperidine-1-carboxylate(0.32 g, 0.51 mmol) in trifluoroacetic acid (5.0 mL) was stirred at 100°C. for 1 hour. The reaction was cooled to ambient temperature and themixture was concentrated in vacuo. The obtained residue was dissolved in1,4-dioxane:aqueous ammonia (5 mL:5 mL, 23% in water) and then stirredat ambient temperature for 16 hours. The reaction mixture wasconcentrated in vacuo to provideN-methyl-2-(4-{[(3R,6S)-6-methylpiperidin-3-yl]amino}-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-oxazole-4-carboxamideas a pale yellow gummy liquid (0.15 g, crude): MS (ES) m/z 355.2 (M+H).

Step 5: Preparation of2-(4-(((3R,6S)-1-(2-cyanoacetyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide

A solution of 2-cyanoacetic acid (0.3 g, 0.27 mmol),1-hydroxy-1,2-dihydropyridin-2-one (0.03 g, 0.27 mmol) and2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate(TBTU) (0.11 g, 0.34 mmol) in N-methylpyrrolidone (3.0 mL) was stirredat ambient temperature for 2 minutes.N-Methyl-2-(4-{[(3R,6S)-6-methylpiperidin-3-yl]amino}-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-oxazole-4-carboxamide(0.08 g, 0.23 mmol) was added followed by triethylamine (0.1 mL, 0.70mmol) and the mixture was stirred at ambient temperature for 16 hours.The reaction mixture was diluted with ethyl acetate, washed with waterand brine. The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude was purified by reversephase purification to obtain2-(4-(((3R,6S)-1-(2-cyanoacetyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamideas a white solid (0.03 g, 30% yield): ¹H NMR (400 MHz, DMSO-d₆, VT at80° C.) δ 11.46 (br s, 1H), 8.46-8.53 (m, 3H), 8.03 (br s, 1H), 7.21 (s,1H), 6.68 (s, 1H), 4.40-4.70 (m, 1H), 3.92-4.01 (m, 5H), 2.84 (d, J=4.0Hz, 3H), 1.80-2.10 (m, 3H), 1.20-1.35 (m, 4H); MS (ES) m/z 422.4 (M+H).

Analytical Conditions:

Mobile phase A: 0.1% NH₄OH in H₂O

Mobile phase B: MeCN

Column: X-Bridge, C18 19*100*5 micron

Flow rate: 20 mL/min

Example 31: Preparation of2-(4-(((3R,5S)-1-(2-cyanoacetyl)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide

Step 1: Preparation of ethyl2-(4-(((3R,5S)-1-((benzyloxy)carbonyl)-5-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylate

A stirred solution of ethyl2-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-oxazole-4-carboxylate(7.0 g, 16.6 mmol) (obtained from Example 29, Step 1),N-methylpyrrolidone (42 mL), benzyl(3S,5R)-3-amino-5-methylpiperidine-1-carboxylate (5.36 g, 21.6 mmol) andtriethylamine (11.7 mL, 82.9 mmol) in a sealed tube was heated to 150°C. for 32 hours. The reaction mixture was cooled to ambient temperature,quenched with water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over annhydrous sodium sulfate, filteredand concentrated in vacuo. The crude was purified using flashchromatography (ethyl acetate/hexane) to provide ethyl2-(4-(((3R,5S)-1-((benzyloxy)carbonyl)-5-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylateas a pale yellow semi solid (5.8 g, 55% yield): MS (ES) m/z 634.3 (M+H).

Step 2: Preparation of2-(4-(((3R,5S)-1-((benzyloxy)carbonyl)-5-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylicacid

To a stirred solution of benzyl(3R,5S)-3-({5-[4-(ethoxycarbonyl)-1,3-oxazol-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)-5-methylpiperidine-1-carboxylate(5.8 g, 9.15 mmol) in methanol:tetrahydrofuran (20 mL:20 mL), was added2M aqueous solution of lithium hydroxide monohydrate (0.8 g, 18.3 mmol)and the mixture was stirred at ambient temperature for 5 hours.Volatiles were removed in vacuo, the residue was dissolved in water andacidified with 10% NaHSO₄ solution and adjusted pH-2. The aqueous layerwas extracted with dichloromethane, washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to provide2-(4-(((3R,5S)-1-((benzyloxy)carbonyl)-5-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylicacid as an off-white solid (5.7 g, crude): MS (ES) m/z 606.3 (M+H).

Step 3: Preparation of benzyl(3S,5R)-3-methyl-5-((5-(4-(methylcarbamoyl)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A solution of2-(4-{[(3R,5S)-1-[(benzyloxy)carbonyl]-5-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-oxazole-4-carboxylicacid (5.7 g, 9.41 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.29 g, 0.74 mmol) in N,N-dimethylformamide(60 mL) was stirred at ambient temperature for 3 minutes. Methylaminehydrochloride (1.27 g, 18.8 mmol) was added followed byN,N-diisopropylethylamine (8.22 mL, 47.0 mmol) and the mixture wasstirred at ambient temperature for 10 hours. The reaction mixture wasdiluted with ethyl acetate, washed with water and brine. The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo. The crude material was purified by flash chromatography (30%ethyl acetate/hexane) to provide benzyl(3S,5R)-3-methyl-5-((5-(4-(methylcarbamoyl)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a pale yellow sticky solid (5.7 g, 97% yield): MS (ES) m/z 619.3(M+H).

Step 4: Preparation ofN-methyl-2-(4-(((3R,5S)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide

A stirred solution of benzyl(3S,5R)-3-methyl-5-((5-(4-(methylcarbamoyl)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(5.7 g, 9.21 mmol) in trifluoroacetic acid (15 mL) was heated at 100° C.for 1 hour in a sealed tube. After cooling, the reaction mixture wasconcentrated to dryness, the residue was dissolved in 1,4-dioxane:aqammonia (10 mL:20 mL, 23% in water) and the reaction mixture stirred atambient temperature for 15 hours. The reaction was concentrated todryness in vacuo to provideN-methyl-2-(4-(((3R,5S)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide as an off-white solid. (9.2 g, crude): MS (ES) m/z355.4 (M+H).

Step 5: Preparation of2-(4-(((3R,5S)-1-(2-cyanoacetyl)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide

A solution of cyanoacetic acid (1.48 g, 17.4 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (11 g, 28.9 mmol) in N,N-dimethylformamide(45 mL) was stirred at ambient temperature for 10 minutes. ThenN-methyl-2-(4-(((3R,5S)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide(4.1 g, 11.6 mmol) was added followed by N,N-diisopropylethylamine (10mL, 57.8 mmol) and the resulting mixture was stirred at ambienttemperature for 12 hours. The reaction was quenched with ice water andextracted with ethyl acetate and the combined organic portion was washedwith water and brine, and dried over anhydrous sodium sulfate. Thesolution was filtered and concentrated in vacuo. The crude material waspurified using reverse phase chromatography to give a white solid (0.67g, 13% yield): ¹H NMR (400 MHz, DMSO-d₆, VT at 90° C.) δ 11.40 (s, 1H),8.54 (s, 1H), 8.47-8.43 (m, 2H), 7.85 (br s, 1H), 7.21 (s, 1H), 6.72 (s,1H), 4.80 (br s, 1H), 4.15 (s, 1H), 3.98 (s, 2H), 3.75 (br s, 1H), 2.85(s, 3H), 2.65 (s, 1H), 2.30-2.27 (m, 2H), 1.86 (br s, 1H), 1.41 (d,J=11.2 Hz, 1H), 0.95 (d, J=5.6 Hz, 3H); MS (ES) m/z 422.3 (M+H).

Analytical Conditions:

Column: X-BridgeC-18 (250 mm×4.6 mm×5 mic)

Mobile phase(A): 0.1% Ammonia in water

Mobile phase(B): MeCN

Flow rate: 1.0 mL/min

Example 32: Preparation of2-(4-(((3S,5R)-1-(2-cyanoacetyl)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide

2-(4-(((3S,5R)-1-(2-cyanoacetyl)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamidewas prepared following the same method as Example 31 and using benzyl(3R,5S)-3-amino-5-methylpiperidine-1-carboxylate in Step 1 to give awhite solid (0.6 g, 11% yield): ¹H NMR (400 MHz, DMSO-d₆, VT at 80° C.)δ 11.45 (s, 1H), 8.45-8.43 (m, 3H), 7.91 (br s, 1H), 7.21 (s, 1H), 6.72(s, 1H), 4.80 (br s, 1H), 4.15 (s, 1H), 3.98 (s, 2H), 3.75 (br s, 1H),2.85 (s, 3H), 2.65 (s, 1H), 2.30-2.27 (m, 2H), 1.86 (br s, 1H), 1.41 (d,J=11.2 Hz, 1H), 0.95 (d, J=5.6 Hz, 3H); MS (ES) m/z 422.3 (M+H).

Analytical Conditions:

Column: X-BridgeC-18 (250 mm×4.6 mm×5 mic)

Mobile phase(A): 0.1% Ammonia in water

Mobile phase(B): MeCN

Flow rate: 1.0 mL/min

Example 33: Preparation of(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide

Step 1: Preparation of ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylate

To a stirred solution of tert-butyl(R)-3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(1.2 g, 2.28 mmol) and ethyl oxazole-4-carboxylate (0.38 g, 2.74 mmol)in 1,4-dioxane (18 mL), was added palladium acetate (0.03 g, 0.12 mmol),CyJohnphos (0.08 g, 0.23 mmol) and cesium carbonate (1.48 g, 4.56 mmol)and the resulting mixture was heated in a sealed tube at 110° C. for 16hours under a nitrogen atmosphere. The reaction mixture was cooled toambient temperature, filtered through celite, washed with ethyl acetateand the filtrate concentrated in vacuo. The crude material was purifiedusing flash chromatography (40% ethyl acetate/hexane) to provide ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylateas an off-white solid (1.1 g, 41% yield): MS (ES) m/z 585.9 (M+H).

Step 2: Preparation of(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid

To a stirred solution of ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylate (0.5g, 0.85 mmol) in ethanol (12 mL) was added a 2M aqueous solution ofsodium hydroxide (0.1 g, 2.56 mmol) and the resulting mixture wasstirred at ambient temperature for 3 hours. Volatiles were removed invacuo, the residue was dissolved in water and acidified with 10%solution of potassium bisulphate and adjusted to pH-3. The aqueous layerwas extracted with dichloromethane and washed with brine. The organiclayer was dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo to provide(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid as an off-white solid. (0.3 g, 64% yield): MS (ES) m/z 557.9 (M+H).

Step 3: Preparation of tert-butyl(R)-3-((5-(4-(methylcarbamoyl)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A solution of(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylicacid (0.27 g, 0.48 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.24 g, 0.63 mmol) in N,N-dimethylformamide(10 mL) was stirred for 5 minutes. Methylamine hydrochloride (0.05 g,0.726 mmol) was added followed by N,N-diisopropylethylamine (0.25 mL,1.45 mmol) and the resulting mixture was stirred at ambient temperaturefor 3 hours. The reaction was quenched with ice water, extracted withethyl acetate, and the organic portion washed with water and brine, andthen dried over anhydrous sodium sulfate. The solution was filtered andconcentrated in vacuo. The crude material was purified using flashchromatography (5% methanol/dichloromethane) to provide tert-butyl(R)-3-((5-(4-(methylcarbamoyl)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a yellow oil (0.27 g, 99% yield): MS (ES) m/z 571.3 (M+H).

Step 4: Preparation of(R)—N-methyl-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide

A solution of tert-butyl(R)-3-((5-(4-(methylcarbamoyl)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.30 g, 0.52 mmol) in dichloromethane:trifluoroacetic acid (5 mL: 4 mL)was stirred at ambient temperature for 3 hours. The reaction mixture wasconcentrated in vacuo and the residue was dissolved in1,4-dioxane:aqueous ammonia (4 mL:5 mL, 23% in water). The reactionmixture was stirred at ambient temperature for 16 hours. The reactionwas concentrated in vacuo to provide a residue which was dissolved in 5%methanol/dichloromethane. The organic layer was washed with water, brineand dried over anhydrous sodium sulfate. The solution was filtered andconcentrated in vacuo to provide(R)—N-methyl-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamideas a gummy liquid (0.12 g, 70% yield): MS (ES) m/z 341.2 (M+H).

Step 5: Preparation of(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide

A solution of cyanoacetic acid (0.05 g, 0.55 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.17 g, 0.45 mmol) in N,N-dimethylformamide(5 mL) was stirred for 10 minutes.(R)—N-Methyl-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide(0.12 g, 0.35 mmol) was added followed by N,N-diisopropylethylamine(0.18 mL, 1.05 mmol) and the resulting mixture was stirred at ambienttemperature for 6 hours. The reaction was quenched with ice water andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The crude material was purified by reverse phase chromatography toprovide(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamideas a white solid (0.01 g, 8% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.68-11.64 (br s, 1H), 8.63 (d, J=7.2 Hz, 1H), 8.55-8.52 (m, 2H), 8.13(s, 1H), 7.24 (s, 1H), 6.72 (s, 1H), 4.38 (br s, 1H), 4.22-4.19 (m, 1H),4.08 (s, 1H), 3.96 (s, 1H), 3.82-3.77 (m, 1H), 3.48 (s, 1H), 3.36 (s,1H), 2.83 (d, J=3.6 Hz, 3H), 2.07 (br s, 2H), 1.85 (br s, 2H); MS (ES)m/z 408.5 (M+H).

Analytical Conditions:

Column: X-Bridge C-18 (250 mm×4.6 mm×5 mic)

Mobile phase(A): 0.1% Ammonia in water

Mobile phase(B): MeCN

Flow rate: 1.0 mL/min.

Example 34: Preparation of(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethyl-oxazole-4-carboxamide

Scheme 32. Preparation of(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethyl-oxazole-4-carboxamide

Step 1: Preparation of tert-butyl(R)-3-((5-(4-(dimethylcarbamoyl)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxylic acid(0.25 g, 0.44 mmol) (obtained from Example 32, Step 2) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.22 g, 0.58 mmol) in N,N-dimethylformamide(10 mL), was added dimethylamine hydrochloride (0.05 g, 0.67 mmol)followed by N,N-diisopropylethylamine (0.23 ml, 1.34 mmol) and themixture stirred at ambient temperature for 30 minutes. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over sodium sulfate, filteredand concentrated in vacuo. The crude was purified by columnchromatography (50% ethyl acetate/hexane) to provide the titled productas yellow oil (0.23 g, 88% yield): MS (ES) m/z 585.3 (M+H).

Step 2: Preparation of(R)—N,N-dimethyl-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide

A solution of tert-butyl(R)-3-((5-(4-(dimethylcarbamoyl)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.23 g, 0.39 mmol) in dichloromethane:trifluoroacetic acid (3 mL:3 mL)was stirred at ambient temperature for 3 hours. The reaction mixture wasconcentrated in vacuo, the residue was dissolved in 1,4-dioxane:aqueousammonia (3 mL:3 mL, 23% in water) and stirred at ambient temperature for16 hours. The reaction mixture was concentrated in vacuo to provide(R)—N,N-dimethyl-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide(0.1 g crude): MS (ES) m/z 355.2 (M+H).

Step 3: Preparation of(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethyl-oxazole-4-carboxamide

To a stirred solution of cyanoacetic acid (0.03 g, 0.33 mmol),1-hydroxy-2-pyridone (0.03 g, 0.27 mmol) and2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate(0.09 g, 0.27 mmol) in N-methylpyrrolidone (5 mL) was added(R)-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide(0.08 g, 0.22 mmol) followed by triethylamine (0.1 mL, 0.7 mmol) and theresulting mixture was stirred at ambient temperature for 2 hours. Thereaction mixture was diluted with water and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The crude waspurified using flash chromatography (10% methanol/hexane) to provide(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethyloxazole-4-carboxamideas an off-white solid (0.05 g, 52% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.4 (br s, 1H), 8.73 (br s, 1H), 8.55 (s, 1H), 8.42 (s, 1H), 7.22 (s,1H), 6.72 (s, 1H), 4.20 (m, 2H), 3.51-3.99 (m, 4H), 3.09-3.29 (m, 6H),1.67-2.15 (m, 5H); MS (ES) m/z 422.1 (M+H).

Example 35: Preparation of(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylthiazole-4-carboxamide

Step 1: Preparation of 2-bromo-N-methylthiazole-4-carboxamide

To a stirred solution of 2-bromothiazole-4-carboxylic acid (1.0 g, 4.8mmol) and1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (4.5 g, 12.0 mmol) in N,N-dimethylformamide(20 mL) was added methylamine (3.6 mL, 7.2 mmol, 2M in tetrahydrofuran)followed by diisopropylethylamine (4.2 mL, 24.0 mmol) and the resultingmixture was stirred at ambient temperature for 16 hours. The reactionmixture was quenched with ice cold water and extracted twice with ethylacetate. The organic layer was washed with brine solution, dried overanhydrous sodium sulfate and concentrated in vacuo. The crude materialwas purified by flash chromatography (13% ethyl acetate/hexane) toprovide 2-bromo-N-methylthiazole-4-carboxamide as a white solid (0.7 g,70% yield): MS (ES) m/z 221.0 (M+H).

Step 2: Preparation of tert-butyl(R)-3-((5-(4-(methylcarbamoyl)thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of 2-bromo-N-methylthiazole-4-carboxamide (0.7 g,1.22 mmol), tert-butyl(R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.4 g, 1.83 mmol, intermediate 7) in 1,4-dioxane (25 mL) was addedtetrakis(triphenylphosphine) palladium(0) (0.14 g, 0.12 mmol) andaqueous solution of 2M sodium carbonate (0.39 g, 3.66 mmol) and thereaction mixture stirred at 100° C. for 16 hours. After cooling, thereaction mixture was diluted with ethyl acetate and filtered throughcelite. The filtrate was washed with water, brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography (35% ethyl acetate/hexane) toprovide tert-butyl(R)-3-((5-(4-(methylcarbamoyl)thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a pale brown liquid (0.55 g, 79% yield): MS (ES) m/z 587.6 (M+H).

Step 3: Preparation of(R)—N-methyl-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-4-carboxamide

A solution of tert-butyl(R)-3-((5-(4-(methylcarbamoyl)thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.55 g, 0.94 mmol) in dichloromethane:trifluoroacetic acid (2.0 mL:3.0mL) was stirred at ambient temperature for 3 hours. The reaction mixturewas concentrated in vacuo, the obtained residue was dissolved in1,4-dioxane:aqueous ammonia (2.0 mL:5.0 mL, 23% in water) and was thenstirred at ambient temperature for 16 hours. The reaction mixture wasconcentrated in vacuo to provide(R)—N-methyl-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-4-carboxamideas a yellow liquid (0.36 g, crude): MS (ES) m/z 357.2 (M+H).

Step 4: Preparation of(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylthiazole-4-carboxamide

A solution of cyanoacetic acid (0.1 g, 1.2 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.9 g, 2.5 mmol) in N,N-dimethylformamide(10 mL) was stirred for 3 minutes. At that time(R)—N-methyl-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-4-carboxamide(0.36 g, 1.0 mmol) was added followed by N,N-diisopropylethylamine (0.72mL, 5.0 mmol) and the mixture stirred at ambient temperature for 16hours. The reaction mixture was quenched with ice cold water andextracted with ethyl acetate. The organic layer was washed with brinesolution, dried over anhydrous sodium sulfate and concentrated in vacuo.The crude material was purified by reverse phase chromatography toprovide(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylthiazole-4-carboxamideas an off-white solid (0.01 g, 3% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.65 (br s, 1H), 9.32 (d, J=7.6 Hz, 1H), 8.37 (s, 1H), 8.30 (s, 1H),8.09 (s, 1H), 7.23 (s, 1H), 6.72 (d, J=8.8 Hz, 1H), 4.27 (s, 1H), 4.11(s, 1H), 4.05 (s, 1H), 3.89 (s, 1H), 3.78 (d, J=12.4 Hz, 1H), 3.64 (s,1H), 3.51 (s, 1H), 3.20-3.23 (m, 3H), 3.00 (s, 1H), 2.83 (s, 3H); MS(ES) m/z 424.2 (M+H).

Analytical Conditions:

Column: X Bridge C18 (100 mm×4.6 mm×3.5 μm)

Mobile phase(A): 0.1% Ammonia in water

Mobile phase(B): MeCN

Flow rate: 0.8 mL/min.

Example 36: Preparation of(R)-3-(3-((5-(5-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of tert-butyl(R)-3-((5-(5-methyloxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A mixture of tert-butyl(R)-3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1l-carboxylate(0.30 g, 5.57 mmol), potassium tert-butoxide (0.13 g, 1.14 mmol)bis(triphenylphosphine)palladium(II) dichloride (0.02 g, 0.03 mmol) and5-methyloxazole (0.09 g, 1.14 mmol) in 1,4-dioxane (5 mL) was heated ina sealed tube at 100° C. under nitrogen atmosphere. After 6 hours thereaction was cooled to ambient temperature, diluted with water andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The crude material was purified by flash chromatography (40% ethylacetate/hexane) to provide tert-butyl(R)-3-((5-(5-methyloxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a thick yellow oil (0.2 g, 66% yield): MS (ES) m/z 528.0 (M+H).

Step 2: Preparation of(R)-5-(5-methyloxazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of tert-butyl(R)-3-((5-(5-methyloxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.20 g, 0.37 mmol) in dichloromethane:trifluoroacetic acid (2.0 mL:2.0mL) was stirred at ambient temperature for 3 hours. The reaction mixturewas concentrated in vacuo, the residue was dissolved in1,4-dioxane:aqueous ammonia (3.0 mL:3.0 mL, 23% in water) and stirred atambient temperature for 16 hours. The reaction was concentrated in vacuoto provide(R)-5-(5-methyloxazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a yellow solid (0.17 g, crude): MS (ES) m/z 298.2 (M+H).

Step 3: Preparation of(R)-3-(3-((5-(5-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A solution of cyanoacetic acid (0.02 g, 0.24 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.58 g,0.30 mmol), 1-hydroxybenzotriazole (0.03 g, 0.22 mmol) andN,N-diisopropylethylamine (0.1 mL, 0.6 mmol) in dichloromethane (5 mL)was stirred at ambient temperature for 5 minutes. Then(R)-5-(5-methyloxazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.06 g, 0.20 mmol) was added and the resulting mixture was stirred atambient temperature for 18 hours. The reaction mixture was quenched withwater and extracted with dichloromethane. The organic layer was washedwith water, brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (5% methanol/dichloromethane) to provide(R)-3-(3-((5-(5-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrilean off-white solid (0.01 g, 27% yield): ¹H NMR (400 MHz, DMSO-d₆, VT at100° C.) δ 11.38 (br s, J=9.2 Hz, 1H), 8.98 (br s, 1H), 8.50 (s, 1H),7.19 (s, 1H), 6.91 (s, 1H), 6.66 (s, 1H), 3.90-4.40 (m, 3H), 3.52-3.91(m, 1H), 3.20-3.40 (m, 2H), 2.31 (s, 3H), 1.95-2.10 (m, 2H), 1.50-1.90(m, 3H); MS (ES) m/z 365.1 (M+H).

Example 37: Preparation of(R)-3-(3-((5-(5-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile

Preparation of(R)-3-(3-((5-(5-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile

A solution of(R)-5-(5-methyloxazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.08 g, 0.26 mmol, Example 36, step 2) and acrylonitrile (0.04 g, 0.60mmol), triethylamine (0.1 mL, 0.80 mmol) in ethanol (10 mL) was heatedto 80° C. for 3 hours. The reaction was cooled to ambient temperatureand concentrated in vacuo. The crude was purified by flashchromatography (10% methanol/dichloromethane) to provide(R)-3-(3-((5-(5-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrileas a white solid (0.02 g, 30% yield): ¹H NMR (400 MHz, DMSO-d₆.) δ 11.49(s, 1H), 9.10 (d, J=8 Hz, 1H), 8.46 (s, 1H), 7.16 (s, 1H), 6.96 (s, 1H),6.55 (s, 1H), 4.18-4.20 (m, 1H), 2.92-2.95 (m, 1H), 2.56-2.64 (m, 5H),2.30-2.47 (m, 5H), 1.91-1.20 (m, 1H), 1.60-1.69 (m, 1H), 1.49-1.53 (m,2H); MS (ES) m/z 351.1 (M+H).

Example 38: Preparation of(R)-3-(3-((5-(1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation oftert-butyl(R)-3-((5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

In a sealed tube a stirred solution of4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (1.0 g, 5.64 mmol),tert-butyl (R)-3-aminopiperidine-1-carboxylate (1.69 g, 8.4 mmol) andtriethylamine (2.37 mL, 16.9 mmol) in N-methyl-2-pyrrolidone (15 mL) washeated at 130° C. for 6 hours. The reaction mixture was cooled to roomtemperature, quenched with water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to obtain the crudetert-butyl(R)-3-((5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas an off-white solid (2.3 g, crude): MS (ES) m/z 342.2 (M+H).

Step 2: Preparation of tert-butyl(R,Z)-3-((5-(N′-hydroxycarbamimidoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A suspension of tert-butyl(R)-3-((5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(2.3 g, 6.74 mmol), hydroxylamine hydrochloride (0.70 g, 10.1 mmol) andtriethylamine (1.89 mL, 13.4 mmol) in ethanol (10 mL) was heated at 90°C. for 15 hours under an argon atmosphere. The reaction mixture wascooled to ambient temperature and concentrated in vacuo to removevolatiles. The residue was dissolved in dichloromethane and washed withwater, brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to provide crude tert-butyl(R,Z)-3-((5-(N-hydroxycarbamimidoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a semi solid (1.2 g, crude): MS (ES) m/z 375.0 (M+H).

Step 3: Preparation of tert-butyl(R)-3-((5-(1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A stirred solution of tert-butyl(R,Z)-3-((5-(N′-hydroxycarbamimidoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate (0.5 g, 1.3 mmol), trifluoroacetic acid(0.05 mL) and triethylorthoformate (0.5 mL) was heated at 60° C. for 12hours in a sealed tube. The reaction was cooled to ambient temperature,diluted with dichloromethane and washed with water and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to provide tert-butyl(R)-3-((5-(1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate as an off-white solid (0.25 g, crude): MS (ES)m/z 385.0 (M+H).

Step 4: Preparation of(R)-5-(1,2,4-oxadiazol-3-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of tert-butyl(R)-3-((5-(1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate (0.25 g, 0.6 mmol) indichloromethane:trifluoroacetic acid (5 mL:2 mL) was stirred at ambienttemperature for 3 hours. The reaction mixture was concentrated in vacuoto remove volatiles and neutralized with aqueous ammonia and extractedwith dichloromethane (30 mL). The organic layer was washed with water,brine, dried over anhydrous sodium sulfate, filtered and concentrated invacuo to provide(R)-5-(1,2,4-oxadiazol-3-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a colorless liquid (0.11 g, crude): MS (ES) m/z 285.0 (M+H).

Step 5: Preparation of(R)-3-(3-((5-(1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

To a stirred solution of cyanoacetic acid (0.044 g, 0.52 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.17 g, 0.45 mmol) in N,N-dimethylformamide(15 mL) was added(R)-5-(1,2,4-oxadiazol-3-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.1 g, 0.35 mmol) followed by N,N-diisopropylethylamine (0.19 mL, 1.05mmol) and then the resulting mixture was stirred at ambient temperaturefor 16 hours. The reaction mixture was quenched with water and extractedwith dichloromethane. The organic layer was washed with water, brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The crude material was purified by reverse phase chromatography toprovide(R)-3-(3-((5-(1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.01 g, 9% yield): ¹H NMR (400 MHz, DMSO-d₆ VT at70° C.) δ 11.51 (br s, 1H), 9.56 (s, 1H), 8.73 (s, 1H), 8.34 (s, 1H),7.46 (s, 1H), 7.23 (s, 1H), 6.70 (d, J=3.2 Hz, 1H), 4.05-4.29 (m, 2H),3.89-4.02 (m, 2H), 3.49-3.75 (m, 2H), 3.40-3.51 (m, 2H), 2.10 (br s,1H), 1.64-1.82 (m, 1H); MS (ES) m/z 352.2 (M+H).

Analytical Conditions:

Column: X-BridgeC-18 (250 mm×4.6 mm×5 mic)

Mobile phase(A): 0.1% Ammonia in water

Mobile phase(B): MeCN

Flow rate: 1.0 mL/min

Example 39: Preparation of(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-5-carboxamide

Step 1: Preparation of ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-5-carboxylate

To a stirred solution of tert-butyl(R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(2.5 g, 4.36 mmol) and ethyl 2-bromooxazole-5-carboxylate (1.05 g, 4.80mmol) in dioxane (25 mL) was added bis(triphenylphosphine)palladium(II)dichloride and a 2M aqueous solution of potassium carbonate (1.8 g,13.10 mmol) and the resulting mixture was heated at 110° C. for 16hours. The reaction mixture was cooled to ambient temperature, dilutedwith ethyl acetate, washed with water and brine. The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The crude was purified using flash chromatography (30% ethylacetate/hexane) to provide ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-5-carboxylateas a viscous brown liquid (0.35 g, 14% yield): MS (ES) m/z 586.3 (M+H).

Step 2: Preparation of tert-butyl(R)-3-((5-(5-(methylcarbamoyl)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A solution of ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-5-carboxylate (0.5 g, 0.85mmol) and methylamine (5 mL, 2M in tetrahydrofuran) was stirred atambient temperature for 48 hours. The reaction mixture was concentratedin vacuo to provide tert-butyl(R)-3-((5-(5-(methylcarbamoyl)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a viscous brown liquid (0.1 g, crude): MS (ES) m/z 571.3 (M+H).

Step 3: Preparation of(R)—N-methyl-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-5-carboxamide

A solution of tert-butyl(R)-3-((5-(5-(methylcarbamoyl)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.17 g, 0.29 mmol) in dichloromethane:trifluoroacetic acid (2 mL:2 mL)was stirred at ambient temperature for 3 hours. The reaction mixture wasconcentrated in vacuo, the residue was dissolved in 1,4-dioxane:aqueousammonia (3 mL:3 mL, 23% in water) and stirred at ambient temperature for16 hours. The reaction mixture was concentrated in vacuo to provide(R)—N-methyl-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-5-carboxamideas a gummy liquid (0.2 g, crude): MS (ES) m/z 341.1 (M+H).

Step 4: Preparation of(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-5-carboxamide

A solution of cyanoacetic acid (0.07 g, 0.83 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (0.32 g, 0.83 mmol) in N,N-dimethylformamide(5 mL) was stirred for 5 minutes. Then(R)—N-methyl-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-5-carboxamide(0.19 g, 0.56 mmol) was added followed by N,N-diisopropylethylamine(0.21 mL, 1.67 mmol) and the mixture stirred at ambient temperature for16 hours. The reaction was quenched with water and extracted withdichloromethane. The organic layer was washed with water, brine anddried over anhydrous sodium sulfate. The solution was filtered andconcentrated in vacuo. The crude material was purified by using flashchromatography (6% methanol/dichloromethane) to provide(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-5-carboxamideas an off-white solid (0.03 g, 12% yield): ¹H NMR (400 MHz, DMSO-d₆, 80°C., VT at 80° C.) δ 11.493 (s, 1H), 8.90 (br s, 1H), 8.80 (s, 1H), 8.40(s, 1H), 7.72 (s, 1H) 7.22 (s, 1H), 6.69 (s, 1H), 3.97 (m, 4H), 3.45 (m,5H), 2.80-2.81 (m, 3H), 2.07 (m, 1H), 1.77 (s, 1H); MS (ES) m/z 408.4(M+H).

Example 40: Preparation of3-((3R,5S)-3-((5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of4-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

To a suspension of sodium hydride (10.55 g, 263 mmol, 60% in mineraloil) in THF (400 ml) cooled to 0-5° C. was added4-bromo-1H-pyrrolo[2,3-b]pyridine (40 g, 203 mmol) portion wise forabout 20 minutes. The reaction was stirred for 30 minutes at 0-5° C.Then triisopropylsilyl chloride (64.7 mL, 304 mmol) was added dropwiseover 20 minutes and the reaction was heated to 70° C. for 3 hours. Thereaction was cooled to ambient temperature, diluted with water andextracted with ethyl acetate. The layers were separated and the aqueouslayer re-extracted with ethyl acetate. The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The crude compound was purified by flash chromatography over 230-400mesh silica gel using pet-ether as eluent to afford4-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (70 g, 97%yield) as a colorless liquid: MS (ES) m/z 355.2 (M+H).

Step 2: Preparation of4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

A solution of 4-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine(46 g, 133 mmol) in THE (800 ml) was cooled to −78° C. Thenn-butyllithium (1.2 M in hexanes, titrated by diphenylacetic acidmethod) (167 mL, 200 mmol) was added slowly using a syringe over ˜1hour. The reaction mixture was stirred for 15 minutes at the sametemperature. Then a solution of N-fluorobenzenesulfonamide (84 g, 266mmol) in THE (235 ml) was added slowly, and the reaction stirred for 1hour at the same temperature. The reaction was quenched with aqueoussaturated NH₄Cl solution and diluted with MTBE (235 mL). The reactionwas slowly raised to ambient temperature, the two layers were separated,and aqueous layer was extracted with MTBE (235 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude compound was purified by flash columnchromatography using 230-400 mesh silica gel and pet-ether to afford4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (15.5 g, 40.6%yield) as a pale yellow liquid: MS (ES) m/z 293.4 (M+H).

Step 3: Preparation of5-bromo-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

A solution of 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine(15 g, 51.31 mmol) in THE (600 mL) was cooled to −78° C. Thensec-butyllithium (1.2 M in cyclohexane, 64 mL, 76.97 mmol) was addedslowly over 30 minutes and the mixture stirred for 1 hour. A solution ofcarbon tetrabromide (30.57 g, 92.36 mmol) in THE (45 mL) was addedslowly and the reaction mass stirred for 1 hour at −78° C. The reactionmixture was quenched by slow addition of aqueous saturated NH₄Clsolution, followed by addition of MTBE (150 ml, 10 vol) and warming toambient temperature. The two layers were separated and the aqueous layerextracted with MTBE (150 mL). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Thecrude compound was purified by flash column chromatography using 230-400mesh silica gel and pet-ether to afford5-bromo-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (15.6g, 82% yield) as pale yellow liquid: MS (ES) m/z 371.3; 373.3 (1:1;M+H).

Step 4: Preparation of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine

A solution of5-bromo-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (26 g,70.08 mmol) in THE (260 mL) was cooled to 0-5° C. using an ice bath.Then tetrabutylammonium fluoride (1.0 M in THF; 84 ml) was added slowlyover 30 minutes and the reaction mass stirred for 4 hours. The reactionmixture was diluted with water (260 mL) and extracted with ethyl acetate(2×130 mL) The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The crude compound waspurified by flash column using 230-400 mesh silica gel and 15-20% ethylacetate in pet-ether to afford5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (11 g, 73% yield) as a paleyellow solid: MS (ES) m/z 215.1; 217.1 (1:1; M+H).

Step 5: Preparation of5-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

A suspension of sodium hydride (2.94 g, 73.6 mmol, 60% in mineral oil)in DMF (110 mL) was cooled to 0-5° C. using an ice salt mixture. To theabove suspension was added 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine(11 g, 51.1 mmol) portion wise and the reaction mixture stirred for 30minutes at the same temperature. Then 2-(trimethylsilyl)ethoxymethylchloride (13.83 g, 82 mmol) was added dropwise using an additionalfunnel over 30 minutes and the reaction stirred at ambient temperaturefor 4 hours. The reaction mixture was poured into cold water andextracted with ethyl acetate (2×). The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The crude compound was purified by flash chromatography using 100-200mesh silica gel using pet-ether as eluent to afford5-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(16 g, 91% yield) as a pale yellow liquid: MS (ES) m/z 345.1; 347.1(1:1; M+H).

Step 6: Preparation of benzyl(3R,5S)-3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidine-1-carboxylate

Benzyl (3R,5S)-3-amino-5-methylpiperidine-1-carboxylate (13.85 g, 55.8mmol) was added to a stirred solution of5-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(16 g, 46.5 mmol) in dimethyl sulfoxide (96 mL) under a nitrogenatmosphere. The reaction mass was stirred for 10 min at ambienttemperature followed by the addition of N, N-diisopropylethylamine (20.7mL, 116.2 mmol). The reaction mixture was slowly heated to 125-130° C.and maintained for 24 hours under a nitrogen atmosphere. The reactionmixture was cooled to room temperature and poured in chilled water (240mL), stirred for 15 minutes and ethyl acetate (160 mL) added. Theorganic layer was separated and the aqueous layer extracted with ethylacetate (100 mL). The combined organic layers were washed with water(2×100 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to provide crude product as very thick syrupymass. The crude product was purified by column chromatography using100-200 mesh silica gel to obtain benzyl(3R,5S)-3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidine-1-carboxylate(19.5 g, 73.3% yield) as a pale yellow viscous mass: MS (ES) m/z 573.3;575.4 (1:1; M+H).

Step 7: Preparation of benzyl(3R,5S)-3-((5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidine-1-carboxylate

To a stirred solution of benzyl(3R,5S)-3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidine-1-carboxylate(0.6 g, 1.05 mmol) and1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.38 g, 1.57 mmol) in 1,4-dioxane (35 mL) was addedbis-(triphenylphosphine)palladium(II) dichloride (0.15 g, 0.21 mmol) and2M aqueous solution of potassium phosphate tribasic (0.90 g. 4.18 mmol)and the mixture heated at 80° C. for 16 hours under a nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,diluted with ethyl acetate and filtered through celite. The filtrate waswashed with water, brine, dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. The crude material was purified by usingflash chromatography (50% ethyl acetate/hexane) to provide benzyl(3R,5S)-3-({5-[1-(difluoromethyl)-1H-pyrazol-3-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)-5-methylpiperidine-1-carboxylateas a viscous pale yellow liquid (0.52 g, 81% yield): MS (ES) m/z 611.3(M+H).

Step 8: Preparation of5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-N-((3R,5S)-5-methylpiperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of benzyl(3R,5S)-3-({5-[1-(difluoromethyl)-1H-pyrazol-3-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)-5-methylpiperidine-1-carboxylate(0.56 g, 0.90 mmol) in trifluoroacetic acid (5 mL) was stirred at 100°C. for 1 hour. The reaction was cooled to ambient temperature and themixture was concentrated in vacuo. The residue was dissolved in1,4-dioxane:aqueous ammonia (5 mL:5 mL) and stirred at ambienttemperature for 16 hours. The reaction mixture was concentrated in vacuoto provide5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-N-((3R,5S)-5-methylpiperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a gum (0.53 g, crude): MS (ES) m/z 347.2 (M+H).

Step 9: Preparation of3-((3R,5S)-3-((5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile

A solution of cyanoacetic acid (0.11 g, 1.3 mmol),1-hydroxybenzotriazole (0.16 g, 1.04 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.25 g,1.30 mmol) in dichloromethane (10 mL) was stirred at ambient temperaturefor 5 minutes. Then5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-N-((3R,5S)-5-methylpiperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.23 g, 0.86 mmol) was added followed by triethylamine (0.36 mL 2.60mmol) and then the resulting mixture was stirred at ambient temperaturefor 16 hours. The reaction mixture was quenched with water and extractedwith dichloromethane. The organic layer was washed with water, brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The crude material was purified using reverse phase chromatography toobtain3-[(3R,5S)-3-({5-[1-(difluoromethyl)-1H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)-5-methylpiperidin-1-yl]-3-oxopropanenitrileas a white solid (0.04 g, 11% yield); ¹H NMR (400 MHz, DMSO-d₆, VT at90° C.) δ 11.17 (br s, 1H), 8.14-8.37 (m, 3H), 7.63-7.94 (m, 1H), 7.16(s, 1H), 7.01 (s, 1H), 6.67 (s, 1H), 4.80-4.83 (m, 1H), 3.60-4.36 (m,3H), 2.66-2.83 (m, 1H), 2.18-2.39 (m, 2H), 1.65-1.93 (m, 1H), 1.11-1.26(m, 2H), 0.91 (d, J=6.4 Hz, 3H); MS (ES) m/z 414.4 (M+H).

Analytical Conditions:

Flow rate: 20.0 mL/min

Column: Sunfire C18 19*150*5 micron

Mobile Phase (A): 0.1% TFA in water

Mobile Phase (B): MeCN

Example 41: Preparation of(R)-3-(3-((5-(isothiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of tert-butyl(R)-3-((5-(isothiazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of tert-butyl(R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.72 g, 1.25 mmol) and 3-bromoisothiazole (0.3 g, 1.63 mmol) in1,4-dioxane (20 mL) was added tetrakis(triphenyl phosphine)palladium(0)(0.18 g, 0.25 mmol) followed by 2M aqueous solution of sodium carbonate(0.4 g, 3.77 mmol) and the reaction mixture heated at 100° C. for 16hours. After cooling the reaction mixture was diluted with ethyl acetateand filtered through celite. The filtrate was washed with water, brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The crude material was purified by flash chromatography (25% ethylacetate/hexane) to provide tert-butyl(R)-3-((5-(isothiazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a pale yellow liquid (0.23 g, 35% yield): MS (ES) m/z 529.9 (M+H).

Step 2: Preparation of(R)-5-(isothiazol-3-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A stirred solution of tert-butyl(R)-3-((5-(isothiazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.3 g, 0.56 mmol) in dichloromethane:trifluoroacetic acid (3.0 mL:3.0mL) was stirred at ambient temperature for 5 hours. The reaction mixturewas concentrated in vacuo, the residue was dissolved in1,4-dioxane:ammonia (3.0 mL:3.0 mL, 23% in water) and stirred at ambienttemperature for 16 hours. The reaction mixture was concentrated todryness to provide(R)-5-(isothiazol-3-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a viscous brown liquid (0.22 g, crude): MS (ES) m/z 300.0 (M+H).

Step 3: Preparation of(R)-3-(3-((5-(isothiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A solution of cyanoacetic acid (0.1 g, 1.00 mmol),1-hydroxybenzotriazole (0.15 g, 1.10 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.21 g,1.10 mmol) in dichloromethane (20 mL) was stirred at ambient temperaturefor 5 minutes. Then(R)-5-(isothiazol-3-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.22 g, 0.73 mmol) was added followed by N,N-diisopropylethylamine (0.4mL, 2.20 mmol) and the resulting mixture stirred at ambient temperaturefor 16 hours. The reaction mixture was quenched with water and extractedwith dichloromethane. The organic layer was washed with water, brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The crude material was purified by flash chromatography (3%methanol/dichloromethane) to provide(R)-3-(3-((5-(isothiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.04 g, 16% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.48 (br s, 1H), 9.58 (d, J=6.0 Hz, 1H), 9.08 (d, J=4.4 Hz, 1H), 8.6(d, J=12.0 Hz, 1H), 7.99 (d, J=4.8 Hz, 1H), 7.19 (s, 1H), 6.67 (s, 1H),4.39 (s, 1H), 4.02-3.95 (m, 6H), 2.02 (s, 1H), 1.72-1.60 (m, 3H); MS(ES) m/z 367.1 (M+H).

Example 42: Preparation of ethyl(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate

Step 1: Preparation of4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbothioamide

A suspension of4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(2.0 g, 6.1 mmol) and Lawesson's reagent (3.73 g, 9.20 mmol) intetrahydrofuran (20 mL) was stirred at ambient temperature for 30minutes. The reaction mixture was diluted with water and extracted withethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo. The crude waspurified by flash chromatography to provide4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbothioamideas a yellow solid (1 g, 50% yield): MS (ES) m/z 342.1 (M+H).

Step 2: Preparation of ethyl2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate

To a stirred solution of4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbothioamide(0.9 g, 2.63 mmol) and ethyl 2-chloro-3-oxopropanoate (0.39 g, 2.63mmol) in toluene (10 mL) was added magnesium sulfate (0.317 g, 2.63mmol) and the mixture was heated to 110° C. for 1 hour under a nitrogenatmosphere. The reaction was cooled to ambient temperature, diluted withwater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate, filtered and concentrated invacuo. The crude material was purified by flash chromatography (20%ethyl acetate/hexane) to provide ethyl2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylateas a yellow solid (0.8 g, 70% yield): MS (ES) m/z 438.1 (M+H).

Step 3: Preparation of ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate

In a 20 mL microwave vial, ethyl2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate(0.60 g, 1.37 mmol), tert-butyl (R)-3-aminopiperidine-1-carboxylate(0.411 g, 2.05 mmol), palladium(II) acetate (0.05 g, 0.20 mmol),(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (0.13 g, 0.20 mmol),sodium tert-butoxide (0.39 g, 4.11 mmol) and 1,4-dioxine (7 mL) werecombined and the resulting mixture subjected to microwave irradiation at80° C. for 1 hour. The reaction was cooled to ambient temperature,diluted with water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The crude was purified using flash chromatography(40% ethyl acetate/hexane) to provide ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylateas a viscous brown liquid (0.23 g, 28% yield): MS (ES) m/z 602.3 (M+H).

Step 4: Preparation of ethyl(R)-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate

A solution of ethyl2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate(0.15 g, 0.24 mmol) in dichloromethane:trifluoroacetic acid (3.0 mL:3.0mL) was stirred at ambient temperature for 3 hours. The reaction mixturewas concentrated in vacuo, the residue was dissolved in1,4-dioxane:aqueous ammonia (5.0 mL: 4.0 mL, 23% in water) and stirredat ambient temperature for 16 hours. The reaction was concentrated invacuo to provide ethyl(R)-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylateas a brown solid (0.15 g, crude): MS (ES) m/z 372.1 (M+H).

Step 5: Preparation of ethyl(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate

To a stirred solution of cyanoacetic acid (0.05 g, 0.60 mmol),1-hydroxy-2-pyridone (0.05 g, 0.48 mmol) and2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate(0.15 g, 0.48 mmol) in N-methylpyrrolidone (5 mL), was added ethyl2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate(0.15 g, 0.40 mmol) followed by triethylamine (0.16 mL, 1.21 mmol) andthe stirring continued at ambient temperature for 2 hours. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over sodium sulfate, filteredand concentrated in vacuo. The crude was purified by flashchromatography (10% methanol/dichloromethane) to provide ethyl(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylateas a pale yellow solid (0.02 g, 10% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.57 (s, 1H), 9.71 (m, 1H), 8.43-8.34 (m, 2H), 7.20 (s, 1H), 6.69 (s,1H), 4.30-4.35 (q, J=6.4 Hz, 2H), 4.02 (m, 1H), 3.79-3.87 (m, 2H), 3.56(m, 1H), 3.39 (m, 1H), 2.03 (m, 2H), 1.77 (m, 2H), 1.62 (m, 2H),1.29-1.33 (t, J=7.2 Hz, 3H); MS (ES) m/z 439.1 (M+H).

Example 43: Preparation of(R)-3-(3-((5-(2-methoxypyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of tert-butyl(R)-3-((5-(2-methoxypyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of tert-butyl(R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(1.36 g, 2.38 mmol) and 4-bromo-2-methoxypyrimidine (0.30 g, 1.58 mmol)in 1,4-dioxane (15 mL) was added bis(triphenylphosphine) palladium(II)dichloride (0.22 g, 0.32 mmol) and 2M aqueous solution of potassiumcarbonate (0.87 g, 6.32 mmol) and the mixture stirred at 105° C. for 15hours. The reaction mixture was cooled to ambient temperature, dilutedwith ethyl acetate, washed with water, brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography (30% ethyl acetate/hexane) toprovide tert-butyl(R)-3-((5-(2-methoxypyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a viscous pale yellow liquid (0.62 g, 70% yield): MS (ES) m/z 555.5(M+H).

Step 2: Preparation of(R)-5-(2-methoxypyrimidin-4-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of tert-butyl(R)-3-((5-(2-methoxypyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.3 g, 0.54 mmol) in dichloromethane:trifluoroacetic acid (3 mL:3 mL)was stirred at ambient temperature for 3 hours. The reaction mixture wasconcentrated in vacuo, the obtained residue was dissolved in1,4-dioxane:aqueous ammonia (3 mL:3 mL, 23% in water) and then stirredat ambient temperature for 16 hours. The reaction mixture wasconcentrated in vacuo to provide(R)-5-(2-methoxypyrimidin-4-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a gummy brown liquid (0.18 g, crude): MS (ES) m/z 325.2 (M+H).

Step 3: Preparation of(R)-3-(3-((5-(2-methoxypyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A solution of cyanoacetic acid (0.03 g, 0.32 mmol),2-hydroxypyridine-N-oxide (0.03 g, 0.32 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.11 g, 0.32 mmol) in N-methylpyrrolidone (4 mL) was stirred at ambienttemperature for 5 minutes. Then(R)-5-(2-methoxypyrimidin-4-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.08 g, 0.25 mmol) was added followed by triethylamine (0.1 mL, 0.74mmol). The resulting mixture was stirred at ambient temperature for 16hours, quenched with water and extracted with dichloromethane. Theorganic layer was washed with water, brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (5% methanol/dichloromethane) toprovide(R)-3-(3-((5-(2-methoxypyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.04 g, 15% yield): ¹H NMR (400 MHz, DMSO-d₆, VTat 100° C.) δ 11.27 (br s, 1H), 9.89 (br s, 1H), 8.44-8.59 (m, 2H), 7.55(s, 1H), 7.15 (s, 1H), 6.66 (s, 1H), 4.16-4.27 (m, 2H), 4.39 (s, 2H),3.83-3.87 (m, 2H), 3.45-3.55 (m, 2H), 2.05-2.10 (m, 2H), 1.58-1.95 (m,4H); MS (ES) m/z 392.2 (M+H).

Example 44: Preparation of(R)-3-(3-((5-(6-aminopyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of tert-butyl (6-bromopyridin-2-yl)carbamate

Sodium bis(trimethylsilyl)amide (6.1 mL, 6.13 mmol, 1.0 M in THF) wasadded to a solution of 6-bromopyridin-2-amine (0.70 g, 4.09 mmol) intetrahydrofuran (15 mL) at −78° C. and the mixture stirred for 0.5hours. A solution of di-tert-butyl dicarbonate (0.98 g, 4.50 mmol)dissolved in tetrahydrofuran (5 mL) was added at −78° C. and then themixture was slowly warmed to ambient temperature and stirred for 16hours. The reaction mixture was quenched with saturated ammoniumchloride and extracted with ethyl acetate. The organic layer was washedwith water, brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (20% ethyl acetate/hexane) to provide tert-butyl(6-bromopyridin-2-yl)carbamate as a colorless semi solid: ¹H NMR (400MHz, DMSO-d₆) δ 10.07 (s, 1H), 7.76-7.78 (m, 1H), 7.62-7.66 (m, 1H),7.20-7.22 (m, 1H), 1.44 (s, 9H); MS (ES) m/z 174.2 (M-Boc).

Step 2: Preparation of tert-butyl(R)-3-((5-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of tert-butyl(R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(1.2 g, 2.19 mmol) and tert-butyl (6-bromopyridin-2-yl)carbamate (0.4 g,1.58 mmol) in 1,4-dioxane (40 mL) was added bis(triphenylphosphine)palladium(II) dichloride (0.2 g, 0.29 mmol) and 2M aqueous solution ofpotassium carbonate (0.81 g, 5.84 mmol) and the mixture was stirred at100° C. for 16 hours. The reaction mixture was cooled to ambienttemperature, diluted with ethyl acetate, washed with water, brine, driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Thecrude material was purified by flash chromatography (30% ethylacetate/hexane) to provide tert-butyl(R)-3-((5-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a gummy pale liquid (0.42 g, 45% yield): MS (ES) m/z 639.4 (M+H).

Step 3: Preparation of(R)-5-(6-aminopyridin-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of tert-butyl(R)-3-((5-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.42 g, 0.66 mmol) in dichloromethane:trifluoroacetic acid (4 mL: 4 mL)was stirred at ambient temperature for 3 hours. The reaction mixture wasconcentrated in vacuo, the residue was dissolved in 1,4-dioxane:aqueousammonia (5 mL:5 mL, 23% in water) and the solution stirred at ambienttemperature for 16 hours. The reaction mixture was concentrated in vacuoto provide(R)-5-(6-aminopyridin-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas an off-white solid (0.45 g, crude): MS (ES) m/z 309.2 (M+H).

Step 4: Preparation of(R)-3-(3-((5-(6-aminopyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A solution of cyanoacetic acid (0.07 g, 0.84 mmol),2-hydroxypyridine-N-oxide (0.08 g, 0.71 mmol) and2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate(0.27 g, 0.84 mmol) in N-methylpyrrolidone (5 mL) was stirred at ambienttemperature for 5 minutes. Then(R)-5-(6-aminopyridin-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.08 g, 0.25 mmol) was added followed by triethylamine (0.27 mL, 1.95mmol) and the resulting mixture stirred at ambient temperature for 18hours. The reaction mixture was quenched with water and extracted withethyl acetate. The organic layer was washed with water, brine, driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Thecrude material was purified by flash chromatography (10%methanol/dichloromethane) to provide(R)-3-(3-((5-(6-aminopyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.11 g, 45% yield): ¹H NMR (400 MHz, DMSO-d₆, VTat 70° C.) δ 11.11 (br s, 1H), 9.58 (br s, 1H), 8.19 (s, 1H), 7.44 (s,1H), 7.10 (s, 1H), 6.85 (s, 1H), 6.57 (s, 1H), 634-6.36 (m, 1H), 5.79(s, 2H), 4.20-4.35 (m, 1H), 3.95-4.07 (m, 1H), 3.45-3.60 (m, 2H),2.10-2.15 (m, 2H), 1.60-1.75 (m, 2H), 1.15-1.30 (m, 3H); MS (ES) m/z376.2 (M+H).

Example 45: Preparation of3-((3R)-3-((5-(5-(methylsulfinyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of 5-(methylthio)thiazol-2-amine

A solution of 5-bromothiazol-2-amine (4.5 g, 25.14 mmol) and sodiumthiomethoxide (3.52 g, 50.28 mmol) in N,N-dimethylformamide (30 mL) wasstirred at 50° C. for 5 hours. The reaction mixture was cooled toambient temperature, diluted with ethyl acetate, washed with water andbrine. The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude was purified using flashchromatography (30% ethyl acetate/hexane) to provide5-(methylthio)thiazol-2-amine as a brown solid (1.5 g, 41% yield): ¹HNMR (400 MHz, CDCl₃) δ 7.08 (s, 1H), 2.36 (s, 3H).

Step 2: Preparation of 2-bromo-5-(methylthio)thiazole

To a stirred solution of 5-(methylthio)thiazol-2-amine (1.5 g, 10.27mmol) in acetonitrile (60 mL) was added tert-butyl nitrite (1.58 g,15.40 mmol) at 0° C. and the mixture stirred for 15 minutes. Copper (II)bromide (6.87 g, 30.81 mmol) was added and the mixture stirred at 0° C.for 3 hours. The reaction mixture was diluted with ethyl acetate, washedwith water and brine. The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The crude was purifiedusing flash chromatography (5% ethyl acetate/hexane) to provide2-bromo-5-(methylthio)thiazole as an orange oil (0.75 g, 34% yield): MS(ES) m/z 209.8; 211.0 (1:1; M+H).

Step 3: Preparation of 2-bromo-5-methanesulfinyl-1,3-thiazole

A solution of 2-bromo-5-(methylthio)-1,3-thiazole (0.59 g, 2.81 mmol)and meta-chloroperoxybenzoic acid (0.48 g, 2.81 mmol) in dichloromethane(20 mL) was stirred at ambient temperature for 1 hour. The reactionmixture was quenched with saturated bicarbonate solution and stirred for30 minutes. The organic layer was separated, washed with water, brine,dried over sodium sulfate, filtered and concentrated in vacuo to obtain2-bromo-5-methanesulfinyl-1,3-thiazole (0.35 g crude) as a viscouscolorless liquid: MS (ES) m/z 226.0; 228.0 (1:1; M+H).

Step 4: Preparation of tert-butyl(3R)-3-((5-(5-(methylsulfinyl)thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of(3R)-1-methyl-N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-amine(1.5 g, 2.62 mmol) and 2-bromo-5-methanesulfinyl-1,3-thiazole (0.39 g,1.75 mmol) in N,N-dimethylformamide (4.00 mL) was added1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (0.28 g, 0.35 mmol) and cesium fluoride (1.06 g,6.99 mmol) and the resulting mixture heated at 80° C. for 5 hours. Thereaction mixture was cooled to ambient temperature, diluted with ethylacetate, washed with water and brine. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudewas purified using flash chromatography (50% ethyl acetate/hexane) toprovide tert-butyl(3R)-3-{[5-(5-methanesulfinyl-1,3-thiazol-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}piperidine-1-carboxylateas a brown colored liquid (0.12 g, 11%, yield): MS (ES) m/z 593.4 (M+H).

Step 5: Preparation of5-(5-(methylsulfinyl)thiazol-2-yl)-N—((R)-piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of tert-butyl(3R)-3-{[5-(5-methanesulfinyl-1,3-thiazol-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}piperidine-1-carboxylate(0.12 g, 0.20 mmol) in dichloromethane:trifluoroacetic acid (2 mL:2 mL)was stirred at ambient temperature for 3 hours. The reaction mixture wasconcentrated in vacuo, the obtained residue was dissolved in1,4-dioxane:aqueous ammonia (3 mL:3 mL, 23% in water) and then stirredat ambient temperature for 16 hours. The reaction mixture wasconcentrated in vacuo to provide(3R)—N-[5-(5-methanesulfinyl-1,3-thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-amineas a gummy solid (0.2 g, crude): MS (ES) m/z 362.1 (M+H).

Step 6: Preparation of3-((3R)-3-((5-(5-(methylsulfinyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A solution of 2-cyanoacetic acid (0.04 g, 0.45 mmol) and1-hydroxybenzotriazole (0.05 g, 0.30 mmol) in dichloromethane (5 mL) wasstirred for 2 minutes. Then(3R)—N-[5-(5-methanesulfinyl-1,3-thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-amine(0.1 g, 0.3 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (0.08 g, 0.41 mmol) and triethylamine (0.11 g, 1.11 mmol)were added and the mixture stirred at ambient temperature for 16 hours.The reaction mixture was quenched with water and extracted with ethylacetate. The organic layer was washed with water, brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by reverse phase chromatography to provide3-((3R)-3-((5-(5-(methylsulfinyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas a pale yellow solid (5 mg, 4% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.73 (br s, 1H), 9.65 (br s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 8.07 (s,1H), 7.24 (s, 1H), 6.71 (s, 1H), 5.91-6.11 (m, 1H), 5.31 (s, 1H),4.12-4.50 (m, 1H), 3.75-4.22 (m, 2H), 3.42-3.72 (m, 2H), 2.95-3.12 (m,3H), 1.95-2.10 (m, 1H), 1.45-1.82 (m, 2H); MS (ES) m/z 429.2 (M+H).

Analytical Conditions:

Flow rate: 0.3 mL/min

Column Ascentis Express C18 (50 mm×2.1 mm×2.73 μm)

Mobile Phase (A): 0.1% Formic acid in water

Mobile Phase (B): MeCN

Example 46: Preparation of(R)-3-(3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of 2-bromo-5-(methylsulfonyl)thiazole

A solution of 2-bromo-5-(methylthio)-1,3-thiazole (0.59 g, 2.81 mmol)and meta-chloroperoxybenzoic acid (1.2 g, 7.02 mmol) in dichloromethane(20 mL) was stirred at ambient temperature for 3 hours. The reactionmixture was quenched with saturated bicarbonate solution and stirred for30 minutes. The organic layer was separated, washed with water, brine,dried over sodium sulfate, filtered and concentrated in vacuo to obtain2-bromo-5-methanesulfonyl-1,3-thiazole (0.35 g crude) as an off-whitesolid (0.45 g, 70% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (s, 1H),3.45 (s, 3H).

Step 2: Preparation of tert-butyl(R)-3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A solution of tert-butyl(R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(1.7 g, 3.09 mmol), potassium carbonate (1.14 g, 8.28 mmol),bis(triphenylphosphine)palladium(II) dichloride (0.30 g, 0.41 mmol) and2-bromo-5-(methylsulfonyl)thiazole (0.5 g, 2.07 mmol) in 1,4-dioxane (50mL) was heated in sealed tube at 110° C. under a nitrogen atmosphere.After 16 hours the reaction was cooled to ambient temperature, dilutedwith water and extracted with ethyl acetate. The organic layer waswashed with brine, dried over sodium sulfate, filtered and concentratedin vacuo. The crude material was purified by flash chromatography (ethylacetate/hexane) to provide tert-butyl(R)-3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a viscous brown liquid (0.55 g, 30% yield): MS (ES) m/z 608.3 (M+H).

Step 3: Preparation of(R)-5-(5-(methylsulfonyl)thiazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of tert-butyl(R)-3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.55 g, 0.91 mmol) in dichloromethane:trifluoroacetic acid (5.0 mL:5.0mL) was stirred at ambient temperature for 3 hours. The reaction mixturewas concentrated in vacuo, the residue was dissolved in1,4-dioxane:aqueous ammonia (5 mL:5 mL) and stirred at ambienttemperature for 16 hours. The reaction mixture was concentrated in vacuoto provide(R)-5-(5-(methylsulfonyl)thiazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a gummy brown solid (0.6 g, crude): MS (ES) m/z 378.1 (M+H).

Step 4: Preparation of(R)-3-(3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

To a stirred solution of cyanoacetic acid (0.03 g, 0.39 mmol),1-hydroxy-2-pyridone (0.03 g, 0.31 mmol) and2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate(0.10 g, 0.31 mmol) in N-methylpyrrolidone (5 mL) was added(R)-5-(5-(methylsulfonyl)thiazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.1 g, 0.26 mmol) followed by triethylamine (0.11 mL, 0.79 mmol) andthe resulting mixture stirred at ambient temperature for 2 hours. Thereaction mixture was diluted with water and extracted with ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo. The crude was purified bycolumn chromatography to provide(R)-3-(3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas a yellow solid (0.01 g, 10% yield): ¹H NMR (400 MHz, DMSO-d₆, VT at100° C.) δ 11.58 (br s, 1H), 9.65 (br s, 1H), 8.42 (s, 1H), 8.24 (s,1H), 7.21 (s, 1H), 6.71 (s, 1H), 3.54-4.44 (m, 6H), 3.42 (s, 3H),1.21-2.04 (m, 5H); MS (ES) m/z 445.1 (M+H).

Example 47: Preparation of(R)-3-(3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile

Preparation of(R)-3-(3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile

To a solution of(R)-5-(5-(methylsulfonyl)thiazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.1 g, 0.26 mmol, Example 46, step 3) in ethanol (3 mL) was addedacrylonitrile (0.14 g, 2.65 mmol) and triethylamine (0.06 ml, 0.79 mmol)and the solution stirred at 80° C. for 3 hours. The reaction was cooledto ambient temperature and concentrated in vacuo. The crude material waspurified by reverse phase chromatography to provide(R)-3-(3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrileas an off-white solid (0.03 g, 25%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.83(br s, 1H), 9.12 (br s, 1H), 8.45 (s, 1H), 8.24 (s, 1H), 7.10 (s, 1H),6.69 (s, 1H), 4.32 (s, 1H), 3.24 (s, 3H), 2.95-3.07 (m, 1H), 2.65-2.85(m, 2H), 2.37-2.67 (m, 4H), 1.80-2.04 (m, 2H), 1.16-1.30 (s, 3H); MS(ES) m/z 431.2 (M+H).

Analytical Conditions:

Flow rate: 20.0 ml/min

Column: Ascentis Express C18 (50 mm×2.1 mm×2.7 μm)

Mobile Phase (A): 1% Ammonia in water

Mobile Phase (B): MeCN

Example 48: Preparation of(R)-3-(3-((5-(5-(methylsulfonyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1. Preparation of ethyl4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred suspension of sodium hydride (2.14 g, 89.28 mmol, 60% inmineral oil) in N,N-dimethylformamide (75 mL) was added ethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (10 g, 44.64 mmol) at0° C. After stirring for 0.5 hour, 2-(trimethylsilyl)ethoxymethylchloride (8.7 mL, 55.34 mmol) was added at 0° C. and the reactionstirred for 2 hours. The reaction was quenched with ice water andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, filtered and concentrated. The crude was purified usingflash chromatography (15% ethyl acetate/hexane) to provide ethyl4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as acolorless liquid (7.8 g, 49% yield): MS (ES) m/z 355.1 (M+H).

Step 2: Preparation of4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid

To a solution of ethyl4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(7.8, 21.91 mmol) in methanol (80 mL) was added 2M aqueous solution ofsodium hydroxide (4.38 g, 109.55 mmol) and the mixture stirred atambient temperature for 5 hours. The reaction was concentrated to removevolatiles to obtain a residue which was dissolved in water and acidifiedwith 1N hydrochloric acid to adjust pH-3. The aqueous layer wasextracted with ethyl acetate, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to provide4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid as an off-white solid (6.3 g, 88% yield): MS (ES) m/z: 327.1 (M+H).

Step 3: Preparation of4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

A solution of4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (6.3 g, 19.32 mmol) and carbonyldiimidazole (4.7 g, 28.98 mmol) indimethylformamide (30 mL) was stirred at ambient temperature for 1 hour.Ammonia (10 mL, 23% in water) was added followed byN,N-diisopropylethylamine (5.0 mL, 28.98 mmol) and the solution stirredfor 3 hours. The reaction was quenched with ice water and extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated. The crude was purified using flashchromatography (30% ethyl acetate/hexane) to provide an off-white solid(4.56 g, 72%, yield): MS (ES) m/z: 326.1 (M+H).

Step 4: Preparation of4-chloro-N-(2,2,2-trichloro-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

A solid mixture of4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(3.0 g, 9.21 mmol) and 2,2,2-trichloroacetaldehyde (1.36 g, 9.21 mmol)was heated to 90° C. until complete melting. The reaction mixture wascooled to ambient temperature and the crude product was purified usingflash chromatography (30% ethyl acetate/hexane) to provide4-chloro-N-(2,2,2-trichloro-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamideas an off-white solid (2 g, 47% yield): MS (ES) m/z: 474.2 (M+H).

Step 5: Preparation of4-chloro-N-(1,2,2,2-tetrachloroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

To a solution of4-chloro-N-(2,2,2-trichloro-1-hydroxyethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(1.30 g, 2.75 mmol) in dichloromethane (30 mL) was added thionylchloride (0.24 mL, 3.30 mmol) and the solution stirred at ambienttemperature. After 3 hours the reaction was concentrated in vacuo undera nitrogen atmosphere to provide4-chloro-N-(1,2,2,2-tetrachloroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamideas a colorless gum (1.35 g, crude). The crude product was taken to nextstep without further purification.

Step 6: Preparation of(2,2-dichloro-1-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamido)vinyl)triphenylphosphoniumchloride

To a stirred solution of4-chloro-N-(1,2,2,2-tetrachloroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(1.35 g, 2.75 mmol) in toluene (30 mL) was added triphenylphosphine(0.72 g, 2.75 mmol) and the solution was heated to 80° C. After 3 hoursthe reaction was cooled to ambient temperature and concentrated in vacuoto provide (2,2-dichloro-1-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamido)vinyl)triphenylphosphoniumchloride as a colorless gum (2.07 g, crude): MS (ES) m/z: 682.4 (M−Cl).

Step 7: Preparation of2-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(triphenyl-λ⁵-phosphanylidene)-4,5-dihydro-1,3-oxazole-5-thione

To a stirred solution of(2,2-dichloro-1-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamido)vinyl)triphenylphosphoniumchloride (2.0 g, 2.78 mmol) in methanol (45 mL) was added sodiumhydrosulfide (0.5 g, 8.80 mmol) and the mixture stirred at ambienttemperature. After 3 hours the reaction mixture was diluted with ethylacetate and washed with water and brine. The organic layer was driedover anhydrous sodium sulfate, filtered and concentrated. The crude waspurified using flash chromatography (50% ethyl acetate/hexane) toprovide2-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(triphenyl-X-phosphanylidene)-4,5-dihydro-1,3-oxazole-5-thioneas a pale yellow thick liquid (1.23 g, 65% yield): MS (ES) m/z: 642.2(M+H).

Step 8: Preparation of(2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(methylthio)oxazol-4-yl)triphenylphosphoniumiodide

To a stirred solution of2-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(triphenyl-λ⁵-phosphanylidene)-4,5-dihydro-1,3-oxazole-5-thione(1.35 g, 2.10 mmol) in methanol (30 mL) was added iodomethane (0.9 g,6.31 mmol) and the mixture stirred at ambient temperature for 16 hours.The reaction mixture was concentrated in vacuo to dryness to provide[2-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(methylsulfanyl)-1,3-oxazol-4-yl]triphenylphosphaniumiodide as a viscous pale yellow liquid (1.50 g, crude): MS (ES) m/z:656.2 (M−I).

Step 9: Preparation of2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(methylthio)oxazole

To a stirred solution of2-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(methylsulfanyl)-1,3-oxazol-4-yl]triphenylphosphaniumiodide (1.50 g, 2.28 mmol) in methanol (2 mL) was added 2 M aqueoussolution of sodium hydroxide (0.36 g, 9.13 mmol) and the solutionstirred at ambient temperature for 2 hours. The reaction mixture wasdiluted with ethyl acetate, washed with water, brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by flash chromatography (10% ethyl acetate/hexane)to provide2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(methylthio)oxazoleas a pale yellow liquid (0.22 g, 24% yield): MS (ES) m/z: 396.1 (M+H).

Step 10: Preparation of tert-butyl(R)-3-((5-(5-(methylthio)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

In a 10 mL vial, a solution of2-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(methylsulfanyl)-1,3-oxazole(0.4 g, 1.01 mmol), tert-butyl (3R)-3-aminopiperidine-1-carboxylate (0.4g, 2.02 mmol) and N,N-diisopropylethylamine (0.39 g, 3.03 mmol) inN-methyl-2-pyrrolidone (10 mL) was heated to 140° C. for 16 hours. Thereaction mixture was cooled to ambient temperature, diluted with ethylacetate and washed with water and brine. The organic layer was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Thecrude material was purified using flash chromatography (30% ethylacetate/hexane) to provide tert-butyl(3R)-3-({5-[5-(methylsulfanyl)-1,3-oxazol-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)piperidine-1-carboxylateas a viscous brown liquid (0.41 g, 72% yield): MS (ES) m/z: 560.5 (M+H).

Step 11: Preparation of tert-butyl(R)-3-((5-(5-(methylsulfonyl)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of tert-butyl(3R)-3-({5-[5-(methylsulfanyl)-1,3-oxazol-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)piperidine-1-carboxylate(0.38 g, 0.68 mmol) in tetrahydrofuran:water (10 mL:3 mL) was addedoxone (1.68 g, 2.72 mmol) and the mixture stirred at ambient temperaturefor 16 hours. The reaction mixture was diluted with ethyl acetate,washed with water and brine. The organic layer was dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The crude waspurified using flash chromatography (40% ethyl acetate/hexane) toprovide tert-butyl(3R)-3-{[5-(5-methanesulfonyl-1,3-oxazol-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}piperidine-1-carboxylateas a pale yellow gummy solid (0.32 g, 80% yield): MS (ES) m/z: 592.5(M+H).

Step 12: Preparation of(R)-5-(5-(methylsulfonyl)oxazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of tert-butyl(3R)-3-{[5-(5-methanesulfonyl-1,3-oxazol-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}piperidine-1-carboxylate(0.26 g, 439 μmol) in dichloromethane:trifluoroacetic acid (5 mL:5 mL)was stirred at ambient temperature for 3 hours. The mixture wasconcentrated in vacuo, the residue was dissolved in 1,4-dioxane:aqueousammonia (5 mL:5 mL (23% in water) and the solution stirred at ambienttemperature for 16 hours. The reaction mixture was concentrated in vacuoto dryness to provide(3R)—N-[5-(5-methanesulfonyl-1,3-oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-amineas a colorless gummy solid (0.32 g, 80% yield): MS (ES) m/z: 362.2(M+H).

Step 13: Preparation of(R)-3-(3-((5-(5-(methylsulfonyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A solution of 2-cyanoacetic acid (0.04 g, 0.45 mmol) and1-hydroxybenzotriazole (0.06 g, 0.4 mmol) in dichloromethane (10 mL) wasstirred for 2 minutes. Then(3R)—N-[5-(5-methanesulfonyl-1,3-oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-amine(0.11 g, 0.30 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (0.09 g, 0.46 mmol) and triethylamine (0.18 mL, 1.12 mmol)were added and the mixture stirred at ambient temperature for 16 hours.The reaction mixture was quenched with water and extracted with ethylacetate. The organic layer was washed with water, brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by reverse phase chromatography to provide3-[(3R)-3-{[5-(5-methanesulfonyl-1,3-oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}piperidin-1-yl]-3-oxopropanenitrileas an off-white solid (0.03 g, 60% yield): ¹H NMR (400 MHz, DMSO-d₆, VTat 80° C.) δ 11.58 (br s, 1H), 8.74 (d, J=5.6 Hz, 1H), 8.62 (s, 1H),7.93 (s, 1H), 7.23 (s, 1H), 6.71 (s, 1H), 4.24-4.43 (m, 1H), 3.71-4.05(m, 3H), 3.41-3.55 (m, 6H), 2.80-2.11 (m, 1H), 1.55-1.85 (m, 3H); MS(ES) m/z 429.1 (M+H).

Analytical Conditions:

Flow rate: 0.3 mL/min

Column: Ascentis Express C18 (50 mm×2.1 mm×2.7 μm)

Mobile Phase (A): 0.1% Formic acid in water

Mobile Phase (B): MeCN

Example 49: Preparation of(R)-3-(3-((5-(2-(methylthio)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of tert-butyl(R)-3-((5-(2-(methylthio)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of 4-chloro-2-(methylthio)pyrimidine (0.30 g, 1.87mmol) and tert-butyl(R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(1.07 g, 1.87 mmol) in 1,4-dioxane (40 mL) was added[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complexwith dichloromethane (0.08 g, 0.09 mmol) and potassium carbonate (0.64g, 4.68 mmol) and the mixture heated to 100° C. for 16 hours. Thereaction was cooled to ambient temperature and diluted with ethylacetate and water. The organic layer was separated, dried over sodiumsulfate, filtered and concentrated in vacuo. The crude residue waspurified using flash chromatography (40% ethyl acetate/hexane) toprovide tert-butyl(R)-3-((5-(2-(methylthio)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a yellow liquid (0.5 g, 50% yield): MS (ES) m/z 571.4 (M+H).

Step 2: Preparation of(R)-5-(2-(methylthio)pyrimidin-4-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of tert-butyl(R)-3-((5-(2-(methylthio)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.35 g, 0.61 mmol) in dichloromethane:trifluoroacetic acid (3 mL: 6 mL)was stirred at ambient temperature for 3 hours. The reaction mixture wasconcentrated in vacuo and the residue was dissolved in1,4-dioxane:aqueous ammonia (3 mL:5 mL, 23% in water) and the reactionmixture stirred at ambient temperature for 16 hours. The reaction wasconcentrated in vacuo to provide(R)-5-(2-(methylthio)pyrimidin-4-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a yellow solid (0.3 g, crude): MS (ES) m/z 341.1 (M+H).

Step 3:(R)-3-(3-((5-(2-(methylthio)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A solution of cyanoacetic acid (0.11 g, 1.32 mmol) and(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (0.40 g, 1.05 mmol) in N,N-dimethylformamide(60 mL) was stirred for 3 minutes. Then(R)-5-(2-(methylthio)pyrimidin-4-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.30 g, 0.88 mmol) was added followed by N,N-diisopropylethylamine(0.48 mL, 2.64 mmol). The reaction mixture was stirred at ambienttemperature for 16 hours. The reaction mixture was diluted with ethylacetate and washed with water and brine. The organic layer was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography to provide(R)-3-(3-((5-(2-(methylthio)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas a pale yellow solid (0.03 g, 2% yield): ¹H NMR (400 MHz, DMSO-d₆,) δ11.61 (s, 1H), 9.90-9.92 (m, 1H), 8.50-8.54 (m, 2H), 7.70 (d, J=5.6 Hz,1H), 7.20-7.21 (m, 1H), 6.70 (s, 1H), 4.30-4.33 (m, 1H), 4.05-4.11 (m,1H), 3.68-3.93 (m, 2H), 3.48-3.52 (m, 1H), 3.11-3.23 (m, 1H), 2.98-3.03(m, 1H), 2.56 (s, 3H), 2.15-2.20 (m, 1H), 1.80-1.90 (m, 1H), 1.61-1.70(m, 2H); MS (ES) m/z 408.1 (M+H).

Analytical Conditions:

Flow rate: 0.3 mL/min

Column: BEH C18 (100 mm×2.1 mm×1.7 μm)

Mobile Phase (A): 0.1% Formic acid in water

Mobile Phase (B): MeCN

Example 50: Preparation of2-cyano-N-(1-(4-(4-(((R)-1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)pyrrolidin-3-yl)-N-methylacetamide

Step 1: Preparation of tert-butyl(R)-3-((5-(2-(methylsulfonyl)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a solution of tert-butyl(R)-3-((5-(2-(methylthio)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.6 g, 1.05 mmol, Example 43, step 1) in tetrahydrofuran:water (6 mL:3mL) was added oxone (0.64 g, 4.21 mmol) and the mixture stirred atambient temperature for 16 hours. The reaction mixture was diluted withethyl acetate, washed with water and brine. The organic layer was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Thecrude was purified using flash chromatography (60% ethyl acetate/hexane)to provide tert-butyl(R)-3-((5-(2-(methylsulfonyl)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a brown oil (0.25 g, 39% yield): MS (ES) m/z 603.6 (M+1).

Step 2: Preparation of tert-butyl(3R)-3-((5-(2-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A solution of(R)-3-((5-(2-(methylsulfonyl)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.1 g, 0.17 mmol), tert-butyl methyl(pyrrolidin-3-yl)carbamate (0.04 g,0.20 mmol) and N,N-diisopropylethylamine (0.06 mL, 0.34 mmol) inN,N-dimethylformamide (2 mL) was stirred at 60° C. for 5 hours. Thereaction mixture was cooled to ambient temperature, diluted with ethylacetate, washed with water and brine. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudewas purified using flash chromatography (20% ethyl acetate/hexane) toprovide tert-butyl(3R)-3-((5-(2-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a brown gummy solid (0.07 g, 58% yield): MS (ES) m/z 723.4 (M+1).

Step 3: Preparation of5-(2-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)-N—((R)-piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of tert-butyl(3R)-3-((5-(2-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.15 g mg, 0.21 mmol) in dichloromethane:trifluoroacetic acid (2 mL:2mL) was stirred at ambient temperature for 3 hours. The reaction mixturewas concentrated in vacuo, the obtained residue was dissolved in1,4-dioxane:aqueous ammonia (3 mL:3 mL, 23% in water) and was thenstirred at ambient temperature for 16 hours. The reaction mixture wasconcentrated in vacuo to provide5-(2-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)-N—((R)-piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a pale yellow thick liquid (0.07 g, crude): MS (ES) m/z 393.3 (M+H).

Step 4: Preparation of2-cyano-N-(1-(4-(4-(((R)-1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)pyrrolidin-3-yl)-N-methylacetamide

A solution of 2-cyanoacetic acid (0.02 g, 0.23 mmol),1-hydroxybenzotriazole (0.03 g, 0.20 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.08 g,0.41 mmol) in dichloromethane (5 mL) was stirred at room temperature for3 minutes. Then5-(2-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)-N—((R)-piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.07 g, 0.17 mmol)_and triethylamine (0.07 mL, 0.51 mmol) were addedand the mixture stirred at ambient temperature for 16 hours. Thereaction mixture was quenched with water and extracted with ethylacetate. The organic layer was washed with water, brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by reverse phase chromatography to provide2-cyano-N-(1-(4-(4-(((R)-1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)pyrrolidin-3-yl)-N-methylacetamideas a pale yellow solid (0.02 g, 21% yield): ¹H NMR (400 MHz, DMSO-d₆, VTat 100° C.) δ 11.23 (br s, 1H), 9.49 (br s, 1H), 8.38 (s, 1H), 8.29 (d,J=5.2 Hz, 1H), 7.14 (s, 1H), 7.04 (d, J=5.2 Hz, 1H), 6.65 (s, 1H),4.50-5.00 (m, 2H), 3.72-4.20 (m, 7H), 3.40-3.60 (m, 2H), 2.88 (s, 3H),2.12-2.27 (m, 4H), 1.45-1.80 (m, 5H); MS (ES) m/z 527.5 (M+H).

Analytical Conditions:

Flow rate: 0.8 mL min

Column: XB C18 (100 mm×4.6 mm×3.5 μm)

Mobile Phase (A): 0.1% Ammonia in water

Mobile Phase (B): MeCN

Example 51: Preparation of(R)-3-(3-((5-(2-aminopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of(R)-5-(2-aminopyrimidin-4-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of tert-butyl(R)-3-((5-(2-(methylsulfonyl)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.25 g, 0.41 mmol, Example 50, step 1) indichloromethane:trifluoroacetic acid (3 mL:3 mL) was stirred at ambienttemperature for 3 hours. The reaction mixture was concentrated in vacuo,the residue was dissolved in 1,4-dioxane:aqueous ammonia (5 mL:5 mL, 23%in water) and stirred at ambient temperature for 16 hours. The reactionmixture was concentrated in vacuo to provide(R)-5-(2-aminopyrimidin-4-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a viscous brown liquid (0.3 g, crude): MS (ES) m/z 310.2 (M+H).

Step 2: Preparation of(R)-3-(3-((5-(2-aminopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A solution of 2-cyanoacetic acid (0.04 g, 0.5 mmol),1-hydroxybenzotriazole (0.06 g, 0.45 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.11 g,0.58 mmol) in dichloromethane (5 mL) was stirred at rt for 3 minutes.Then(R)-5-(2-aminopyrimidin-4-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.12 g, 0.39 mmol) was added followed by triethylamine (0.27 mL, 1.95mmol) and the mixture stirred at ambient temperature for 16 hours. Thereaction mixture was quenched with water and extracted with ethylacetate. The organic layer was washed with water, brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by reverse phase chromatography to provide(R)-3-(3-((5-(2-aminopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.02 g, 13% yield): ¹H NMR (400 MHz, DMSO-d₆, VTat 100° C.) δ 11.11 (br s, 1H), 9.95 (br s, 1H), 8.37 (s, 1H), 8.17 (s,1H), 7.12 (s, 1H), 7.00 (s, 1H), 6.26 (s, 1H), 6.22 (s, 2H), 4.20-4.42(m, 2H), 3.20-3.80 (m, 5H), 2.00-2.07 (m, 1H), 1.45-1.80 (m, 3H); MS(ES) m/z 377.4 (M+H).

Analytical Conditions:

Flow rate: 0.8 mL/min

Column: X-Bridge C18 (100 mm×4.6 mm×3.5 μm)

Mobile Phase (A): 0.1% Ammonia in water

Mobile Phase (B): MeCN

Example 52: Preparation of3-((3S,5R)-3-methyl-5-((5-(2-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of4-chloro-N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

A solution of4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (2.00 g, 6.12 mmol) and(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (3.49 g, 9.18 mmol) in N,N-dimethylformamide(25.0 mL) was stirred at ambient temperature for 3 minutes. ThenN,O-dimethylhydroxylamine hydrochloride (1.49 g, 15.3 mmol) was addedfollowed by triethylamine (4.28 mL, 30.6 mmol) and the mixture wasstirred at ambient temperature for 16 hours. The reaction mixture wasdiluted with ethyl acetate and water. The organic layer was separated,washed with water, brine, dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. The crude material was purified using flashchromatography (40% ethyl acetate/hexane) to provide4-chloro-N-methoxy-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamideas a pale yellow liquid (1.82 g, 80% yield): MS (ES) m/z 370.2 (M+H).

Step 2: Preparation of1-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-one

To a solution of4-chloro-N-methoxy-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (2.20 g, 5.95 mmol) in tetrahydrofuran (25 mL),was added bromo(ethynyl)magnesium (18 mL, 8.92 mmol, 3M solution in THF)at 0° C. The reaction mixture was warmed to ambient temperature andstirred for 16 hours. The reaction mixture was quenched with saturatedaqueous ammonium chloride and extracted with ethyl acetate. The organiclayer was washed with water, brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude material was purifiedusing flash chromatography (40% ethyl acetate/hexane) to provide1-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-oneas a pale yellow semi-solid (1.25 g, 63% yield): MS (ES) m/z 335.1(M+H).

Step 3: Preparation of4-chloro-5-(2-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

To a stirred suspension of1-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-one(1.20 g, 3.58 mmol), was added N-chloroethanimidamide (0.5 mg, 5.38mmol) and sodium carbonate (1.14 g, 10.8 mmol) in acetonitrile (10 mL)and the mixture subjected to MW irradiation at 120° C. for 1 hour. Thereaction was cooled to ambient temperature and diluted with ethylacetate and water. The organic layer was separated, washed with water,brine, dried over anhydrous sodium sulfate, filtered and concentrated toobtain a thick gum. The crude material was purified using flashchromatography (40% ethyl acetate/hexane) to provide4-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methylpyrimidineas a brown liquid (0.72 g, 54% yield): MS (ES) m/z 375.1 (M+H).

Step 4: Preparation of benzyl(3S,5R)-3-methyl-5-((5-(2-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

In a 20 mL MW vial a solution of4-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methylpyrimidine(0.6 g, 1.60 mmol), benzyl(3R,5S)-3-amino-5-methylpiperidine-1-carboxylate (0.6 g, 2.40 mmol) andN,N-diisopropylethylamine (0.6 mL 3.20 mmol) in N-methylpyrrolidin-2-one(7 mL) was subjected to microwave irradiation at 190° C. for 6 hours.The reaction was cooled to ambient temperature, diluted with ethylacetate and water. The organic layer was separated, washed with water,brine, dried over anhydrous sodium sulfate, filtered and concentrated.The crude material was purified using flash chromatography (40% ethylacetate/hexane) to provide benzyl(3S,5R)-3-methyl-5-{[5-(2-methylpyrimidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}piperidine-1-carboxylateas a brown thick liquid (0.34 g, 36% yield): MS (ES) m/z 587.6 (M+H).

Step 5: Preparation ofN-((3R,5S)-5-methylpiperidin-3-yl)-5-(2-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of benzyl(3S,5R)-3-methyl-5-{[5-(2-methylpyrimidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}piperidine-1-carboxylate(0.33 g, 0.56 mmol) in trifluoroacetic acid (5 mL) was stirred for 1hour at 100° C. in a sealed tube. After 1 hour the reaction mixture wascooled to ambient temperature and concentrated in vacuo to dryness. Theresidue was dissolved in 1,4-dioxane:aqueous ammonia (5 mL:5 mL) andstirred at ambient temperature for 16 hours. The reaction mixture wasconcentrated to dryness to obtain(3R,5S)-5-methyl-N-[5-(2-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-amineas a colorless gummy solid (0.35 g, crude): MS (ES) m/z 323.2 (M+H).

Step 6: Preparation of3-((3S,5R)-3-methyl-5-((5-(2-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A solution of 2-cyanoacetic acid (0.03 g, 0.32 mol),1-hydroxy-1,2-dihydropyridin-2-one (0.31 g, 0.28 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.1 g, 0.32 mol) in N-methylpyrrolidin-2-one (2 mL) was stirred atambient temperature for 3 minutes. Then(3R,5S)-5-methyl-N-[5-(2-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-amine(0.07 g, 0.22 mmol) was added followed by triethylamine (0.1 mL, 0.70mmol) and the mixture stirred at ambient temperature for 16 hours. Thereaction mixture was diluted with ethyl acetate, washed with water andbrine. The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude material was purifiedusing reverse phase chromatography to obtain3-[(3S,5R)-3-methyl-5-{[5-(2-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}piperidin-1-yl]-3-oxopropanenitrileas a white solid (0.02 g, 20% yield): ¹H NMR (400 MHz, DMSO-d₆, VT at80° C.) δ 11.29 (br s, 1H), 10.38 (br s, 1H), 8.54-8.56 (m, 2H),7.75-7.76 (m, 1H), 7.15 (s, 1H), 6.70 (s, 1H), 4.81-4.84 (m, 1H),3.93-4.33 (m, 5H), 2.65 (s, 4H), 2.27-2.30 (m, 1H), 1.65-1.95 (m, 1H),1.17-1.30 (m, 1H), 0.95 (d, J=6.4 Hz, 3H); MS (ES) m/z 390.4 (M+H).

Analytical Conditions:

Column: X-Bridge, C18 19*100*5 micron

Mobile phase(A): 0.1% Ammonia in H₂O

Mobile phase(B): MeCN

Flow rate: 20.0 mL/min

Example 53: Preparation of(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylthiazole-5-carboxamide

Step 1: Preparation of4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbothioamide

To a solution of4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (7.0 g, 21.5 mmol, Example 48, step 3) in tetrahydrofuran (30 mL)was added Lawesson's reagent (8.70 g, 21.5 mmol) and the mixture stirredat ambient temperature for 3 hours. The reaction mixture was quenchedwith ice cold saturated sodium bicarbonate solution, extracted withethyl acetate and washed with brine. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to provide4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbothioamideas a pale yellow thick liquid (1.5 g, 47% yield): MS (ES) m/z 342.0(M+H).

Step 2: Preparation of ethyl2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate

To a solution of4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbothioamide(6.0 g, 17.5 mmol) in toluene (60 mL) was added ethyl2-chloro-3-oxopropanoate (7.93 g, 52.6 mmol) and magnesium sulfate (4.22g, 35.1 mmol) and the mixture heated to 90° C. for 12 hours. Thereaction was cooled to ambient temperature, quenched with water andextracted with ethyl acetate and washed with brine. The organic layerwas dried over anhydrous sodium sulfate, filtered and concentrated invacuo to provide ethyl2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylateas a viscous brown liquid (0.6 g, 7.81% yield): MS (ES) m/z 438.1 (M+H).

Step 3: Preparation of ethyl2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate

A solution of ethyl2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate(0.50 g, 0.22 mmol) in dichloromethane:trifluoroacetic acid (5 mL:5 mL)was stirred at ambient temperature for 3 hours. The reaction mixture wasconcentrated in vacuo. The residue was dissolved in 1,4-dioxane:aqueousammonia (5 mL:5 mL 23% in water) and the mixture stirred at ambienttemperature for 16 hours. The reaction mixture was concentrated in vacuoto provide ethyl2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate as anoff-white solid (0.52 g, crude): MS (ES) m/z 308.0 (M+H).

Step 4: Preparation of ethyl2-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate

To a stirred solution of ethyl2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate (0.20g, 0.65 mmol), 4-dimethylaminopyridine (0.02 g, 0.13 mmol) andtriethylamine (0.09 mL, 0.65 mmol) in dichloromethane (3 mL) was added4-methyl-benzenesulfonyl chloride (0.15 g, 0.78 mmol) and the reactionmixture stirred at ambient temperature for 3 hours. The reaction mixturewas quenched with saturated sodium bicarbonate solution, extracted withdichloromethane and washed with brine. The organic layer was dried oversodium sulfate, filtered and concentrated in vacuo to afford ethyl2-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylateas a brown solid (0.2 g, 34% yield): MS (ES) m/z 462.1 (M+H).

Step 5: Preparation of ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate

To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.2 g, 0.75 mmol) in ethanol (0.5 mL) was added tert-butyl(R)-3-aminopiperidine-1-carboxylate (0.35 g, 1.73 mmol) andtriethylamine (0.5 mL, 3.6 mmol) and the mixture subjected to microwaveirradiation at 130° C. for 15 minutes. The reaction was cooled toambient temperature, quenched with water and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The crude materialwas purified using flash chromatography (50% ethyl acetate/hexane) toprovide ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylateas a viscous colorless liquid (0.17 g, 62% yield): MS (ES) m/z 626.2(M+H).

Step 6: Preparation of(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylicacid

To a stirred solution of ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate(0.35 g, 0.55 mmol) in ethanol (1 mL) was added a 2M aqueous solution oflithium hydroxide (0.07 g, 2.8 mmol) and the mixture was subjected toheating at 90° C. for 3 hours. The reaction was cooled to ambienttemperature and concentrated in vacuo to remove volatiles. The residualmaterial was dissolved in water and acidified with 1N hydrochloric acidto adjust pH to ˜3. The precipitated solid was filtered, washed withwater and dried in high vacuo to provide(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylicacid as an off-white solid (0.2 g, 83% yield): MS (ES) m/z 444.2 (M+H).

Step 7: Preparation of tert-butyl(R)-3-((5-(5-(methylcarbamoyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A solution of(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylicacid (0.25 g, 0.56 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (0.43 g, 1.12 mmol) in N,N-dimethylformamide (5 mL)was stirred at ambient temperature for 5 minutes. Methylaminehydrochloride (0.07 g, 0.68 mmol) was added followed by triethylamine(0.4 mL, 2.77 mmol) and the mixture stirred for 12 hours. The reactionwas quenched with water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude material was purifiedusing flash chromatography (80% ethyl acetate/hexane) to providetert-butyl(R)-3-((5-(5-(methylcarbamoyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a viscous colorless liquid (0.25 g, 97% yield): MS (ES) m/z 457.2(M+H).

Step 8: Preparation of(R)—N-methyl-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxamidehydrochloride

(R)-3-((5-(5-(Methylcarbamoyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.25 g, 0.54 mmol) was added to 4N hydrochloric acid and 1,4-dioxane (5mL) and the mixture stirred at ambient temperature for 4 hours. Thereaction mixture was concentrated in vacuo and dried to provide(R)—N-methyl-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxamidehydrochloride as an off-white solid (0.16 g, 77% yield): MS (ES) m/z357.3 (M+H)⁺.

Step 9: Preparation of(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylthiazole-5-carboxamide

A solution of cyanoacetic acid (0.04 g, 0.64 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (0.24 g, 0.63 mmol) in N,N-dimethylformamide(4 mL) was stirred at ambient temperature for 3 minutes. Then(R)—N-methyl-2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxamidehydrochloride (0.15 g, 0.42 mmol) was added followed byN,N-diisopropylethylamine (0.5 mL, 1.42 mmol) and the mixture stirred atambient temperature for 16 hours. The reaction was quenched with waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The crude material was purified by reverse phase chromatographyto provide(R)—N-(2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-4-yl)methanesulfonamideas an off-white solid (0.01 g, 6% yield): ¹H NMR (400 MHz, DMSO-d₆, VTat 80° C.) δ 11.45 (s, 1H), 9.65 (br s, 1H), 8.20-8.31 (m, 3H), 7.19 (s,1H), 6.68 (s, 1H), 3.89-4.50 (m, 4H), 3.68 (m, 2H), 3.43 (m, 2H), 2.79(s, 2H), 2.07 (s, 1H), 1.64-1.75 (m, 3H); MS (ES) m/z 424.2 (M+H).

Analytical Conditions:

Column: Ascentis Express C18 (50 mm×2.1 mm×2.7 μm)

Mobile phase(A): 0.1% % Formic acid in water

Mobile phase(B): MeCN

Flow rate: 1.0 mL/min

Example 54: Preparation of(R)—N-(2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-4-yl)N,N-dimethylsulfuric diamide

Step 1: Preparation of [(2-bromopyridin-4-yl)sulfamoyl]dimethylamine

To a solution of 2-bromopyridin-4-amine (2.0 g, 11.5 mmol) in pyridine(20 mL) was added dimethylsulfamoyl chloride (1.63 g, 11.5 mmol) and themixture stirred in a sealed tube at 80° C. for 12 hours under a nitrogenatmosphere. The reaction was cooled to ambient temperature, diluted withethyl acetate and water. The organic layer was separated, washed withbrine, dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The crude residue was purified by flash chromatography (20% ethylacetate/hexane) to provide [(2-bromopyridin-4-yl)sulfamoyl]dimethylamineas a colorless gummy liquid (1.2 g, 37% yield): MS (ES) m/z 280.0 (M+).

Step 2: Preparation of tert-butyl(R)-3-((5-(4-((N,N-dimethylsulfamoyl)amino)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a solution of [(2-bromopyridin-4-yl)sulfamoyl]dimethylamine (0.8 g,2.85 mmol) and tert-butyl(R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(1.96 g, 3.42 mmol) in dioxane (9 mL), was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane(0.1 g, 0.13 mmol) and 2M aqueous solution of potassium carbonate (1.18g, 8.55 mmol) and the mixture heated at 100° C. for 12 hours undernitrogen atmosphere. The reaction was cooled to ambient temperature,diluted with ethyl acetate, washed with water and brine. The organiclayer was dried over anhydrous sodium sulfate, filtered and evaporatedunder reduced pressure to obtain crude compound. The crude residue waspurified using flash chromatography (50% ethyl acetate/hexane) to affordtert-butyl(R)-3-((5-(4-((N,N-dimethylsulfamoyl)amino)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a gummy brown solid (0.25 g, 54% yield): MS (ES) m/z 645.9 (M+H).

Step 3: Preparation of(3R)—N-(5-{4-[(dimethylsulfamoyl)amino]pyridin-2-yl}-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-amine

A solution of tert-butyl(R)-3-((5-(4-((N,N-dimethylsulfamoyl)amino)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.25 g, 0.38 mmol) in dichloromethane:trifluoroacetic acid (5 mL:5 mL)was stirred at ambient temperature for 3 hours. The reaction mixture wasconcentrated in vacuo and the residue was dissolved in1,4-dioxane:aqueous ammonia (5 mL:5 mL 23% in water) and stirred atambient temperature for 16 hours. The reaction mixture was diluted withethyl acetate, washed with water and brine. The organic layer was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo toprovide(R)-5-(5-methyloxazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a gummy yellow solid (0.15 g, crude): MS (ES) m/z 413.9 (M−H).

Step 4: Preparation of(R)—N-(2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-4-yl)N,N-dimethylsulfuric diamide

A solution of cyanoacetic acid (0.036 g, 0.43 mmol) and(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.22 g, 0.43 mmol) in N,N-dimethylformamide(5 mL) was stirred for 5 minutes. Then(R)-5-(5-methyloxazol-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.15 g, 0.36 mmol) was added followed by N,N-diisopropylethylamine(0.19 mL, 1.08 mmol), and the reaction mixture stirred at ambienttemperature for 12 hours. The reaction mixture was diluted with ethylacetate, washed with water and brine. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by reverse phase chromatography to provide3-[(3R)-3-{[5-(4-{[(5-bromo-3-formyl-1H-indol-7-yl)(methyl)sulfamoyl]amino}pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}piperidin-1-yl]-3-oxopropanenitleas an off-white solid (0.01 g, 6% yield): ¹H NMR (400 MHz, DMSO-d₆) δ12.37 (s, 1H), 10.81 (s, 2H), 8.45-8.46 (m, 1H), 8.24-8.26 (m, 1H),7.41-7.48 (m, 2H) 7.16-7.17 (m, 1H), 6.91 (s, 1H), 4.08 (s, 1H),3.60-3.76 (m, 4H), 2.80 (s, 6H), 2.04-21.30 (m, 6H); MS (ES) m/z 483.2(M+H).

Analytical Conditions:

Flow rate: 0.3 mL/min

Column: BEH C18 (50 mm×2.1 mm×1.7 μm)

Mobile Phase (A): 0.1% TFA in water

Mobile Phase (B): MeCN

Example 55: Preparation of(R)-3-(3-((5-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of tert-butyl(R)-3-((5-(5-(methylsulfonyl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of tert-butyl(R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(1.0 g, 1.75 mmol) and 2-bromo-5-(methylsulfonyl)pyridine (0.62 g, 2.6mmol) in 1,4-dioxane (10 mL) was added dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.09 mmol) followed by a 2Maqueous solution of potassium carbonate (0.72 g, 5.25 mmol) and themixture was heated at 90° C. for 12 hours under nitrogen in a sealedtube. The reaction was cooled to ambient temperature, diluted with ethylacetate and water. The organic layer was separated, washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The crude material was purified by flash chromatography (40% ethylacetate/hexane) to provide tert-butyl(R)-3-((5-(5-(methylsulfonyl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a sticky pale yellow solid (0.19 g, 18% yield): MS (ES) m/z 602.3(M+H).

Step 2: Preparation of(R)-5-(5-(methylsulfonyl)pyridin-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of tert-butyl(R)-3-((5-(5-(methylsulfonyl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.19 g, 0.32 mmol) in dichloromethane:trifluoroacetic acid (3 mL:3 mL)was stirred at ambient temperature for 3 hours. The reaction mixture wasconcentrated in vacuo, the residue was dissolved in 1,4-dioxane:aqueousammonia (3 mL:3 mL 23% in water) and the solution stirred at ambienttemperature for 16 hours. The reaction mixture was concentrated in vacuoto provide(R)-5-(5-(methylsulfonyl)pyridin-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine as an off-white solid (0.15 g, crude); MS (ES)m/z 372.2 (M+H).

Step 3: Preparation of(R)-3-(3-((5-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A solution of cyanoacetic acid (0.051 g, 0.6 mmol),N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.085 g,0.6 mmol), 1-hydroxybenzotriazole (0.82 g, 0.6 mmol) andN,N-diisopropylethylamine (0.2 mL, 1.2 mmol) in dichloromethane (15 mL)was stirred at ambient temperature for 5 minutes. Then(R)-5-(5-(methylsulfonyl)pyridin-2-yl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.15 g, 0.4 mmol) was added and the resulting mixture stirred atambient temperature for 12 hours. The reaction mixture was quenched withwater and extracted with dichloromethane. The organic layer was washedwith water, brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by reverse phasechromatography to provide(R)-3-(3-((5-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.03 g, 16% yield): ¹H NMR (400 MHz, DMSO-d₆ VTat 100° C.) δ 11.27 (br s, 1H), 9.96 (br s, 1H), 8.98 (s, 1H), 8.51 (s,1H), 8.24 (d, J=2.2 Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.16 (s, 1H), 6.66(s, 1H), 4.29 (br s, 1H), 3.89 (br s, 2H), 3.40-3.45 (m, 3H), 3.27 (s,3H), 2.08 (br s, 1H), 1.64-1.77 (m, 3H), 1.25 (s, 1H); MS (ES) m/z 439.1(M+H).

Analytical Conditions:

Column: X bridge (250 mm×4.6 mm×5 micron)

Mobile phase(A): 0.1% Ammonia in water

Mobile phase(B): Methanol

Flow rate: 1.0 mL/min

Example 56: Preparation of(R)—N-(2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-4-yl)methanesulfonamide

Step 1: Preparation of N-(2-bromopyridin-4-yl)methanesulfonamide

Methanesulfonyl chloride (0.79 ml, 6.97 mmol) was added to a stirredsolution of 2-bromopyridin-4-amine (1.0 g, 5.81 mmol) and pyridine (1mL) in dichloromethane (5 mL) at 0° C. and the solution warmed toambient temperature and stirred for 12 hours. The reaction mixture wasquenched with ice cold water and extracted with ethyl acetate. Theorganic layer was washed with water, brine and dried over anhydroussodium sulfate. The solution was filtered and concentrated in vacuo. Thecrude material was purified by using flash chromatography (20% ethylacetate/hexane) to provide N-(2-bromopyridin-4-yl)methanesulfonamide asa brown solid (0.4 g, 28% yield): MS (ES) m/z 252.8 (M+H).

Step 2: Preparation of tert-butyl(R)-3-((5-(4-(methylsulfonamido)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a solution of tert-butyl(R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.80 g, 1.39 mmol) and N-(2-bromopyridin-4-yl)methanesulfonamide (0.28g, 1.58 mmol) in 1,4-dioxane (8 mL) was added bis(triphenylphosphine)palladium(II) dichloride (0.09 g, 0.02 mmol) followed by a 2M aqueoussolution of sodium carbonate (0.45 g, 4.17 mmol) and the mixture stirredat 100° C. for 12 hours under a nitrogen atmosphere. The reactionmixture was cooled to ambient temperature, diluted with ethyl acetate,washed with water, brine, dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. The crude material was purified by flashchromatography (30% ethyl acetate/hexane) to provide tert-butyl(R)-3-((5-(4-(methylsulfonamido)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a colorless thick liquid (0.12 g, 12% yield): MS (ES) m/z 616.9(M+H).

Step 3: Preparation of(R)—N-(2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-4-yl)methanesulfonamide

A solution of(R)-3-((5-(4-(methylsulfonamido)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.140 g, 0.22 mmol) in dichloromethane:trifluoroacetic acid (2 mL:2 mL)was stirred at ambient temperature for 3 hours. The reaction mixture wasconcentrated in vacuo, the obtained residue dissolved in1,4-dioxane:aqueous ammonia (2 mL: 4 mL 23% in water) and stirred atambient temperature for 16 hours. The reaction mixture was concentratedin vacuo to provide(R)—N-(2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-4-yl)methanesulfonamideas an off-white solid (0.11 g, crude): MS (ES) m/z 385.1 (M−H)⁺.

Step 4: Preparation of(R)—N-(2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-4-yl)methanesulfonamide

To a stirred solution of cyanoacetic acid (0.036 g, 0.426 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (0.140 g, 0.37 mmol) inN,N-dimethylformamide (5 mL) was added(R)—N-(2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-4-yl)methanesulfonamide(0.11 g, 0.284 mmol) followed by N,N-diisopropylethylamine (0.45 mL,1.42 mmol) and the mixture stirred at ambient temperature for 16 hours.The reaction was quenched with water and extracted with ethyl acetate.The organic layer was washed with water, brine and dried over anhydroussodium sulfate. The solution was filtered and concentrated in vacuo. Thecrude material was purified by reverse phase chromatography to provide(R)—N-(2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-4-yl)methanesulfonamideas an off-white solid (0.02 g, 15% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.37-11.41 (m, 1H), 9.90 (br s, 1H), 8.17-8.31 (m, 3H), 7.40-7.42 (s,1H), 7.15 (s, 1H) 6.94 (s, 1H), 6.61 (s, 1H), 4.04 (m, 1H), 3.92-3.99(m, 3H), 3.55-3.67 (m, 2H), 3.55 (m, 2H), 3.11 (s, 2H), 2.87 (s, 1H),1.97 (s, 2H), 1.60-1.69 (s, 1H); MS (ES) m/z 454.1 (M+H).

Analytical Conditions:

Column: X-BridgeC-18 (250 mm×4.6 mm×5 mic)

Mobile phase(A): 0.1% Ammonia in water

Mobile phase(B): MeCN

Flow rate: 1.0 mL/min

Example 57: Preparation of3-((3R,5S)-3-methyl-5-((5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of4-chloro-N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

A solution of compound4-chloro-1-{[2-(trimethysilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (5.0 g, 15.3 mmol) and[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (11.6 g, 30.6 mmol) in dichloromethane (50mL) was stirred for 5 minutes. Methoxy(methyl)amine (1.40 g, 22.9 mmol)and N,N-diisopropylethylamine (7.99 mL, 45.9 mmol) were added and themixture was stirred at ambient temperature. After 5 hours the reactionmixture was diluted with ethyl acetate, washed with water and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated. The crude material was purified by flash chromatography(20% ethyl acetate/hexane) to provide4-chloro-N-methoxy-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamideas a gummy brown solid (4 g, 71% yield): MS (ES) m/z 370.2 (M+H).

Step 2: Preparation of1-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-yl)ethan-1-one

To a stirred solution of4-chloro-N-methoxy-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(10 g, 27 mmol) in tetrahydrofuran (100 mL) was addedbromo(methyl)magnesium (27 mL 81.1 mmol) at 0° C. and the solutionallowed to stir at ambient temperature for 2 hours. The reaction wasquenched with saturated ammonium chloride solution and extracted withethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated to provide1-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethan-1-one as a paleyellow thick liquid (6.5 g, 68% yield): MS (ES) m/z 325.2 (M+H).

Step 3: Preparation of4-chloro-5-(pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

A mixture of1-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethan-1-one(2.0 g, 6.16 mmol), formamide (6 mL), p-toluenesulfonic acid (0.30 g,1.54 mmol) and bis(trimethylsilyl)amine (1.61 mL, 7.70 mmol) wassubjected to microwave irradiation at 215° C. for 40 minutes. Thereaction mixture was cooled to room temperature and quenched withcrushed ice and extracted with ethyl acetate. The organic layer waswashed with brine, dried over sodium sulfate, filtered and concentratedin vacuo. The crude material was purified by flash chromatography (30%ethyl acetate/hexane to provide4-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidineas a brown solid (0.4 g, 18% yield): MS (ES) m/z 361.1 (M+H).

Step 4: Preparation of4-chloro-5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine

A solution of4-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine(0.80 g, 0.29 mmol) in dichloromethane:trifluoroacetic acid (0.5 mL:2mL) was stirred at ambient temperature for 3 hours. The reaction mixturewas concentrated in vacuo and the residue was dissolved in1,4-dioxane:aqueous ammonia (0.2 mL:2 mL, 23% in water) and the mixturestirred at ambient temperature for 16 hours. The reaction mixture wasconcentrated in vacuo to provide4-chloro-5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine as a brown solid(0.5 g, crude): MS (ES) m/z 231.1 (M+H).

Step 5: Preparation of benzyl(3R,5S)-3-methyl-5-((5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A stirred solution of4-{4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}pyrimidine (0.10 g, 0.43mmol), 1-methylpyrrolidin-2-one (2 mL), benzyl(3S,5R)-3-amino-5-methylpiperidine-1-carboxylate (118 mg, 1.48 mmol) andN,N-diisopropylethylamine (0.1 mL, 0.58 mmol) was heated at 170° C. for32 hours in a 10 mL sealed tube. The reaction mixture was cooled toambient temperature and quenched with water and extracted with ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo to provide benzyl(3R,5S)-3-methyl-5-{[5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}piperidine-1-carboxylateas a brown liquid (0.15 g, 44.57% yield): MS (ES) m/z 443.2 (M+H).

Step 6: Preparation ofN-((3S,5R)-5-methylpiperidin-3-yl)-5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A stirred solution of benzyl(3R,5S)-3-methyl-5-{[5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}piperidine-1-carboxylate(0.25 g, 0.56 mmol) in trifluoroacetic acid (1 mL) was heated to 100° C.for 1 hour in a sealed tube. The reaction mixture was cooled to ambienttemperature and concentrated in vacuo to provideN-((3S,5R)-5-methylpiperidin-3-yl)-5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a colorless gummy solid (0.17 g, 99% yield): MS (ES) m/z 309.2 (M+H).

Step 7: Preparation of3-((3R,5S)-3-methyl-5-((5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A solution of cyanoacetic acid (0.06 g, 0.71 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (0.252 g, 1.07 mmol) inN,N-dimethylformamide (1 mL) was stirred at ambient temperature for 3minutes. Then(3S,5R)-5-methyl-N-[5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-amine(0.22 g, 0.71 mmol) was added followed by N,N-diisopropylethylamine (0.5mL, 2.14 mmol) and the mixture stirred at ambient temperature for 16hours. The reaction mixture was diluted with ethyl acetate, washed withwater and brine. The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The crude material waspurified by reverse phase chromatography to provide3-((3R,5S)-3-methyl-5-((5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl) amino) piperidin-1-yl)-3-oxopropanenitrile as an off-whitesolid (0.012 g, 4.5% yield): ¹H NMR (400 MHz, DMSO-d₆, VT at 80° C.) δ11.36 (s, 1H), 10.06 (br s, 1H), 9.08 (s, 1H), 8.65-8.66 (s, 1H), 8.54(s, 1H), 7.96-7.97 (m, 1H), 7.16 (s, 1H), 6.71 (s, 1H), 4.77 (s, 1H),3.98 (m, 4H), 3.65 (m, 1H), 2.70 (m, 1H), 2.30 (m, 1H), 1.85 (m, 1H),1.29 (m, 1H), 0.93-0.94 (m, 3H); MS (ES) m/z 376.2 (M+H).

Analytical Conditions:

Column: BEH C18 (50 mm×2.1 mm×1.7 μm)

Mobile phase(A): 0.1% Formic acid in water

Mobile phase(B): MeCN

Flow rate: 0.3 mL/min

Example 58: Preparation of(R)-3-(3-((5-(1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of tert-butyl (2-chloroethyl)(methyl)carbamate

To a stirred solution of 2-chloro-N-methylethan-1-amine (4.0 g, 42.9mmol) and triethylamine (17.99 mL, 128.7) in dichloromethane (30 mL) wasadded di-tert-butyl dicarbonate (12.8 mL, 55.8 mmol) and the solutionstirred at ambient temperature for 12 hours. The reaction was quenchedwith water and extracted with ethyl acetate. The organic layer waswashed with water, brine and dried over anhydrous sodium sulfate. Thesolution was filtered and concentrated in vacuo to provide tert-butyl(2-chloroethyl)(methyl)carbamate as a semi solid (3 g, crude).

Step 2: Preparation of tert-butyl(2-((6-bromopyridin-2-yl)oxy)ethyl)(methyl)carbamate

A suspension of 6-bromopyridin-2-ol (2.0 g, 10.4 mmol) and potassiumcarbonate (2.3 g, 17.2 mmol) in N,N-dimethylformamide (15 mL) was addedto tert-butyl (2-chloroethyl)(methyl)carbamate (1.5 g, 8.6 mmol) and themixture was heated to 80° C. for 12 hours. The reaction was cooled toambient temperature, quenched with water and extracted with ethylacetate. The organic layer was washed with water, brine and dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified using flash chromatography (10% ethylacetate/hexane) to provide tert-butyl(2-((6-bromopyridin-2-yl)oxy)ethyl)(methyl)carbamate as a colorlessgummy solid (0.65 g, 26% yield): MS (ES) m/z 330.1; 333.1 (1:1; M+H).

Step 3: Preparation of tert-butyl(R)-(2-((6-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate

To a stirred solution of(R)-3-oxo-3-(3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile(0.2 g, 0.49 mmol, Example 61, step 1), and tert-butyl(2-((6-bromopyridin-2-yl)oxy)ethyl)(methyl)carbamate (0.16 g, 0.49 mmol)in 1,4-dioxane (8 mL) was addedchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.04 g, 0.05 mmol) followed by 2M aqueous solution of potassiumphosphate (0.31 g, 1.46 mmol) and the mixture stirred at 110° C. for 12hours under a nitrogen atmosphere. The reaction mixture was cooled toambient temperature, filtered and concentrated in vacuo. The crudematerial was purified by flash chromatography (5%methanol/chloromethane) to provide tert-butyl(R)-(2-((6-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)oxy)ethyl)(methyl)carbamateas a viscous brown liquid (0.06 g, 23% yield): MS (ES) m/z 534.2 (M+H).

Step 4: Preparation of(R)-3-(3-((5-(6-(2-(methylamino)ethoxy)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrilehydrochloride

A solution of tert-butyl(R)-(2-((6-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate(0.05 g, 0.09 mmol) in dioxane (1 mL): 4N hydrochloride in dioxane (0.5mL) was stirred at ambient temperature for 40 minutes. The reactionmixture was concentrated in vacuo and purified by reverse phasechromatography to provide(R)-3-(3-((5-(6-(2-(methylamino)ethoxy)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrilehydrogen chloride as an off-white solid (0.01 g, 23% yield): ¹H NMR (400MHz, DMSO-d₆) δ 12.14 (br s, 1H), 8.70 (br s, 2H), 8.25-8.27 (m, 1H),7.90-7.93 (m, 1H), 7.37-7.43 (m, 2H), 6.87-6.89 (m, 2H), 4.49-4.52 (m,3H), 4.30 (m, 1H), 3.99-4.10 (m, 3H), 3.75-3.80 (m, 1H), 3.60 (m, 2H),2.79-2.85 (m, 1H), 2.64 (s, 3H), 2.13 (s, 1H), 1.68 (br s, 3H); MS (ES)m/z 434.6 (M+H).

Analytical Conditions:

Kinetex EVO C18 (100 mm×2.1 mm×2.6 μm)

Mobile phase(A): 0.1% trifluoroacetic acid in water

Mobile phase(B): MeCN

Flow rate: 0.75 mL/min

Example 59. Preparation of(R)-3-(3-((5-(3-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Preparation of(R)-3-(3-((5-(3-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

To a stirred solution of(R)-3-(3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile(0.05 g, 0.14 mmol) in 1,4-dioxane (4 mL) was added3-(methylsulfonyl)phenylboronic acid (0.04 g, 0.21 mmol) and 2M aqueoussolution of cesium carbonate (0.13 g, 0.41 mmol) and the mixturedegassed with argon for 15 minutes. Tetrakistriphenylphosphine palladium(0) (0.01 g, 0.07 mmol) was added and the resulting mixture was heatedin a sealed tube at 100° C. for 3 hours. The reaction mixture was cooledto room temperature, filtered through celite and the filtrate wascollected and concentrated in vacuo. The crude was purified by columnchromatography (5% methanol/dichloromethane) to provide(R)-3-(3-((5-(3-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.05 g, 42% yield): ¹H NMR (400 MHz, DMSO-d₆, VTat 70° C.) δ 11.23 (s, 1H), 7.81-7.87 (m, 2H), 7.73 (d, J=6.8 Hz, 3H),7.22 (s, 1H), 6.61 (s, 1H), 4.90 (br s, 1H), 4.11 (br s, 1H), 3.84 (brs, 5H), 3.42 (br s, 1H), 3.21 (s, 3H), 1.93 (br s, 1H), 1.51-1.58 (m,3H); MS (ES) m/z 437.9 (M+H).

Example 60: Preparation of(R)-3-(3-((5-(4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Preparation of(R)-3-(3-((5-(4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

To a solution of(R)-3-(3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile(0.4 g, 1.1 mmol) in N,N-dimethylformamide (10 mL) was added lithiumchloride (0.095 g, 1.1 mmol), 4-methyl-2-(tributylstannyl)pyrimidine(0.50 g, 1.3 mmol), copper iodide (0.021 g, 0.05 mmol), andtetrakis(triphenyl-phosphine)palladium (0) (0.07 g, 0.05 mmol) and theresulting mixture stirred at 120° C. for 3 hours in sealed tube under anitrogen atmosphere. The reaction was cooled to ambient temperature,diluted with ethyl acetate and water. The organic layer was separated,washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by reverse phasechromatography to provide((R)-3-(3-((5-(4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.01 g, 7% yield): ¹H NMR (400 MHz, DMSO-d₆) δ12.09 (br s, 1H), 8.43 (br s, 1H), 8.21 (s, 1H), 7.49 (s, 1H), 7.35 (s,1H), 7.16 (d, J=4.8 Hz, 1H), 6.87 (s, 1H), 4.30-4.55 (m, 1H), 3.55-4.05(m, 3H), 3.30-3.45 (m, 2H), 2.82 (s, 3H), 1.95-2.10 (m, 2H), 1.60-1.85(m, 3H); MS (ES) m/z 376.1 (M+H).

Analytical Conditions:

Column: X-BridgeC-18 (250 mm×4.6 mm×5 mic)

Mobile phase(A): 0.1% Ammonia in water

Mobile phase(B): MeCN

Flow rate: 1.0 mL/min

Example 61: Preparation of(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylisonicotinamide

Step 1: Preparation of(R)-3-oxo-3-(3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile

To a stirred solution of(R)-3-(3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile(0.20 g, 0.55 mmol) in 1,4-dioxane (6 ml) was added4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(0.14 g, 0.57 mmol), potassium phosphate (0.35 g, 1.66 mmol) andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.09 g, 0.11 mmol) and the reaction mixture stirred at 110° C. for 2hours under a nitrogen atmosphere. The reaction was cooled to ambienttemperature, diluted with ethyl acetate and washed with water. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The crude material waspurified by reverse phase chromatography to provide(R)-3-oxo-3-(3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrileas a sticky brown solid (0.45 g, crude).

Step 2: Preparation of(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylisonicotinamide

To a stirred solution of(R)-3-oxo-3-(3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile(0.20 g, 0.49 mmol) in 1,4-dioxane:water (10 mL), was added2-bromo-N-methylisonicotinamide (0.13 g, 0.58 mmol),chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.04 g, 4.89 mmol) and 2M aqueous solution of potassium phosphate (0.31g, 0.15 mmol) and the reaction mixture stirred at 110° C. under anitrogen atmosphere. After 16 hours, the reaction mixture was cooled toambient temperature, diluted with DCM, and filtered through celite. Thefiltrate was concentrated in vacuo and the crude material purified byreverse phase chromatography to provide(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylisonicotinamide as a pale yellow solid (0.08 g, 7% yield): ¹H NMR (400MHz, DMSO-d₆, VT at 80° C.) 11.23 (br s, 1H), 9.83 (br s, 1H), 8.51-8.62(m, 3H), 8.20 (s, 1H), 7.56-7.57 (m, 1H), 7.15 (s, 1H), 6.63 (s, 1H),4.19-4.38 (m, 2H), 3.94 (m, 2H), 3.64 (m, 2H), 3.40-3.45 (m, 2H),2.84-2.85 (m, 2H), 2.02 (br s, 2H), 1.60 (m, 2H); MS (ES) m/z 418.3(M+H)⁺.

Analytical Conditions:

Column: X-Bridge, C18 (19 mm×100 mm×5 mic)

Mobile phase(A): 0.1% Ammonia in water

Mobile phase(B): MeCN

Flow rate: 20.0 mL/min

Preparation of 2-bromo-N-methylpyridine-4-carboxamide

A solution of 2-bromoisonicotinic acid (1.0 g, 4.95 mmol) and(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (2.45 g, 6.44 mmol) in N,N-dimethylformamide(10 mL) was stirred at ambient temperature for 3 minutes. Methylamine(12.4 mL, 24.8 mmol) was added followed by triethylamine (1.04 mL, 7.43mmol) and the mixture stirred at ambient temperature. After 5 hours thereaction mixture was diluted with ethyl acetate, washed with water andbrine. The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated. The crude material was purified by flashchromatography (30% ethyl acetate/hexane) to provide2-bromo-N-methylpyridine-4-carboxamide as a viscous colorless liquid(0.85 g, 3.95 mmol): MS (ES) m/z 214.9 (M+1).

Example 62: Preparation of(R)-3-(3-((5-(1-(2-hydroxyethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of(R)-3-oxo-3-(3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile

To a suspension of(R)-3-(3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile(0.35 g, 0.96 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.36 g,1.45 mmol), potassium phosphate (0.60 g, 2.89 mmol) in 1,4-dioxane (10mL) was addedchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (0.07 g, 0.09 mmol) and themixture heated at 110° C. for 1 hour. The reaction was cooled to ambienttemperature and the mixture was used for next step without work up.

Step 2: Preparation of(R)-3-(3-((5-(1-(2-((4-methoxybenzyl)oxy)ethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

To a stirred mixture of(R)-3-oxo-3-(3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile(˜0.35 g), 3-bromo-1-(2-((4-methoxybenzyl)oxy)ethyl)-1H-pyrazole (0.39g, 1.283 mmol) in dioxane (10 mL) was addedbis(triphenylphosphine)palladium(II) dichloride (0.03 g, 0.04 mmol)followed by a 2M aqueous solution of potassium phosphate (0.54 g, 2.56mmol) and the reaction mixture heated at 110° C. for 12 hours. Thereaction mixture was cooled to ambient temperature, filtered throughcelite and the filtrate concentrated in vacuo. The crude material waspurified using flash chromatography (5% methanol/dichloromethane) toprovide2(R)-3-(3-((5-(1-(2-((4-methoxybenzyl)oxy)ethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas a brown semi-solid (0.2 g, 46% yield): MS (ES) m/z 514.3 (M+H).

Step 3: Preparation of(R)-3-(3-((5-(1-(2-hydroxyethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

To a solution of2(R)-3-(3-((5-(1-(2-((4-methoxybenzyl)oxy)ethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (0.18 g, 0.35mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL)at 0° C. and the mixture stirred at ambient temperature for 3 hours. Thereaction was diluted with dichloromethane, washed with saturated sodiumbicarbonate solution and brine. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by reverse phase chromatography to provide(R)-3-(3-((5-(1-(2-hydroxyethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off white solid (0.01 g, 7% yield): ¹H NMR (400 MHz, DMSO-d₆) δ12.22 (s, 1H), 10.1 (s, 1H), 8.43 (d, J=6.0 Hz, 1H), 7.88 (s, 1H), 7.40(s, 1H), 6.91 (d, J=14.8 Hz, 2H), 4.60 (br s, 1H), 4.32 (br s, 1H),4.22-4.23 (m, 2H), 3.97-4.07 (m, 2H), 3.66-3.79 (m, 4H), 2.11-2.30 (m,2H), 1.77 (m, 4H); MS (ES) m/z 394.4 (M+H).

Analytical Conditions:

Column: X-BridgeC-18 (250 mm×4.6 mm×5 mic)

Mobile phase(A): 0.1% Ammonia in water

Mobile phase(B): MeCN

Flow rate: 1.0 mL/min

Preparation of 3-bromo-1-(2-((4-methoxybenzyl)oxy)ethyl)-1H-pyrazole

Step 1: Preparation of 2-(3-bromo-1H-pyrazol-1-yl)ethan-1-ol and2-(5-bromo-1H-pyrazol-1-yl)ethan-1-ol

A mixture of 3-bromo-1H-pyrazole (2.5 g, 17.123 mmol), 2-bromoethan-1-ol(3.95 g, 31.67 mmol), potassium iodide (4.26 g, 25.68 mmol) andpotassium hydroxide (1.91 g, 34.24 mmol) in ethanol (30 mL) was heatedat 100° C. for 12 hours. The reaction was cooled to ambient temperature,filtered to remove the solid and the filtrate was concentrated in vacuo.The residue was dissolved in ethyl acetate and washed with water, brine,dried over sodium sulfate, filtered and concentrated in vacuo. The crudewas purified by column chromatography (n-hexane: ethanol with 0.1% DEA)to provide 2-(3-bromo-1H-pyrazol-1-yl)ethan-1-ol as a liquid (1.2 g, 37%yield) and 2-(5-bromo-1H-pyrazol-1-yl)ethan-1-ol as a colorless gummysolid (0.8 g, 24%): MS (ES) m/z:191.0 (M+H).

Step 2: Preparation of3-bromo-1-(2-((4-methoxybenzyl)oxy)ethyl)-1H-pyrazole

To a stirred solution of 2-(3-bromo-1H-pyrazol-1-yl)ethan-1-ol (1.2 g,6.34 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride(0.4 g, 9.53 mmol, 60% mineral oil dispersion) at 0° C. After 20 minutes1-(chloromethyl)-4-methoxybenzene (1.48 g, 9.52 mmol) was added at 0° C.and the reaction warmed to ambient temperature for 3 hours. The reactionwas quenched with ice cold water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The crude material waspurified by using flash chromatography (30% ethyl acetate/hexane) toprovide bromo-1-(2-((4-methoxy benzyl)oxy)ethyl)-1H-pyrazole as a paleyellow oil (1.45 g, 73%): MS (ES) m/z 313.3 (M+H).

Example 63: Preparation of(R)-3-(3-((5-(3-(hydroxymethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Preparation of(R)-3-(3-((5-(3-(hydroxymethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

To a stirred solution of(R)-3-(3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile(0.35 g, 0.96 mml) in dioxane (8 mL) was added bis(pinacolato)diboron(0.37 g, 1.45 mmol) and potassium phosphate (0.61 g, 2.9 mmol) followedby XPhos-Pd-G2 (0.08 g, 0.1 mmol). The resulting suspension was heatedto 120° C. for 2 hours. The reaction mixture was cooled to ambienttemperature and then (6-bromopyridin-2-yl)methanol (0.28 g, 1.45 mmol),2M aqueous solution of potassium phosphate (0.41 g, 1.93 mmol) andXPhos-Pd-G2 (0.08 g, 0.1 mmol) were added and the mixture was heated at100° C. for 2 hours. The reaction mass was cooled to ambienttemperature, filtered through celite and washed with ethyl acetate. Thefiltrate was washed with water and brine. The organic layer was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Thecrude material was purified by reverse phase chromatography to provide(R)-3-(3-((5-(3-(hydroxymethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (16 mg, 19% yield): ¹H NMR (400 MHz, DMSO-d₆ at70° C.) δ 11.20 (s, 1H), 9.93-10.08 (m, 1H), 8.38 (s, 1H), 7.82 (m, 1H),7.70 (d, J=8.0 Hz, 1H), 7.29 (d, J=7.23 Hz, 1H), 7.14 (s, 1H), 6.63 (s,1H), 5.25 (s, 1H), 4.63 (d, J=6.0 Hz, 2H), 4.28-4.49 (m, 1H), 3.94-4.02(m, 2H), 3.68-3.75 (m, 1H), 3.54-3.62 (m, 1H), 2.80-2.96 (m, 1H),1.92-2.20 (m, 2H), 1.52-1.86 (m, 3H); MS (ES) m/z: 391.1 (M+H).

Analytical Conditions:

Zorbax-Eclipse XDB C18 (150 mm×4.6 mm×5 μm)

Mobile phase(A): 0.1% ammonia in water

Mobile phase(B): MeCN

Flow rate: 1.0 mL/min

Example 64. Preparation of3-((3R,5S)-3-((5-(6-(hydroxymethyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of benzyl(3S,5R)-3-methyl-5-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of benzyl(3R,5S)-3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidine-1-carboxylate(0.70 g, 1.22 mmol) in toluene (30.0 mL) was addedchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.19 g, 0.24 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(0.68 g, 2.68 mmol) and potassium tert-butoxide (0.34 g, 3.05 mmol) andthe mixture stirred on a pre-heated oil bath at 110° C. for 15 minutes.The reaction was cooled to ambient temperature, diluted with ethylacetate, washed with water and brine. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated to obtain benzyl(3S,5R)-3-methyl-5-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas viscous brown liquid (1.24 g, crude): MS (ES) m/z 621.4 (M+H).

Step 2: Preparation of benzyl(3R,5S)-3-((5-(6-(hydroxymethyl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidine-1-carboxylate

A stirred mixture of benzyl(3S,5R)-3-methyl-5-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(1.20 g, 1.93 mmol), (6-bromopyridin-2-yl)methanol (0.24 mg, 1.29 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.20 g, 0.26 mmol) and 2M aqueous solution of tripotassium phosphate(1.09 g, 5.16 mmol) in 1,4-dioxane (35 mL) was heated at 110° C. for 16hours. The reaction was cooled to ambient temperature and diluted withethyl acetate and water. The organic layer was separated, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudewas purified by combi-flash eluting with 0-50% ethyl acetate/hexane toobtain benzyl(3R,5S)-3-((5-(6-(hydroxymethyl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidine-1-carboxylateas a viscous brown liquid (0.51 g, 66% yield): MS (ES) m/z 602.4 (M+H).

Step 3: Preparation of(6-(4-(((3R,5S)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)methanol

A stirred solution of benzyl(3R,5S)-3-((5-(6-(hydroxymethyl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidine-1-carboxylate(0.56 g, 0.85 mmol) in trifluoroacetic acid (5.0 mL) was heated to 100°C. for 1 hour. The reaction mixture was cooled to ambient temperatureand then concentrated in vacuo, the residue was dissolved in1,4-dioxane:aqueous ammonia (5 mL:5 mL) and stirred at ambienttemperature for 16 hours. The reaction mixture was concentrated in vacuoto provide(6-(4-(((3R,5S)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)methanolas a viscous brown liquid (0.52 g, crude); MS (ES) m/z 338.2 (M+H).

Step 4: Preparation of3-((3R,5S)-3-((5-(6-(hydroxymethyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile

A solution of 2-cyanoacetic acid (0.14 g, 1.69 mmol),1-hydroxybenzotriazole (0.21 mg, 1.35 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.32 g,1.69 mmol) in dichloromethane (4.0 mL) was stirred at ambienttemperature for 3 minutes. Then(6-(4-(((3R,5S)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)methanol(0.38 g, 1.13 mmol) was added followed by triethylamine (1.08 mL, 5.63mmol) and the mixture stirred at ambient temperature for 16 hours. Thereaction mixture was diluted with ethyl acetate, washed with water andbrine. The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude was purified using reversephase chromatography to provide3-((3R,5S)-3-((5-(6-(hydroxymethyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.03 g, 7% yield): ¹H NMR (400 MHz, DMSO-d₆, VTat 80° C.) δ 11.16 (br s, 1H), 10.05 (br s, 1H), 8.39 (s, 1H), 7.79-7.83(m, 1H), 7.70-7.72 (m, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.12 (s, 1H), 6.65(s, 1H), 4.15-4.30 (m, 1H), 4.75-4.85 (m, 1H), 4.60-4.67 (m, 1H),3.87-4.07 (m, 1H), 3.60-3.67 (m, 1H), 3.55 (s, 2H), 2.80-2.90 (m, 1H),2.15-2.25 (m, 2H), 1.65-1.80 (m, 2H), 1.10-1.30 (m, 1H), 0.92 (d, J=6.0Hz, 3H); MS (ES) m/z 405.2 (M+H).

Analytical Conditions:

Flow rate: 0.3 mL/min

Column: Ascentis Express C18 (50 mm×2.1 mm×2.73 μm)

Mobile Phase (A): 0.1% Formic acid in water

Mobile Phase (B): MeCN

Example 65. Preparation of3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of tert-butyl(3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a stirred solution of benzyl(3S,5R)-3-methyl-5-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}piperidine-1-carboxylate(1.0 g, 1.61 mmol) and 2-bromo-5-methanesulfonyl-1,3-thiazole (0.28 g,1.18 mmol) in 1,4-dioxane (30 mL) was addedpalladium(II)bis(triphenylphosphine) dichloride (0.15 g, 0.21 mmol) and2M aqueous solution of tripotassium phosphate (0.91 g, 4.30 mmol) andthe mixture heated to 110° C. for 16 hours. The reaction was cooled toambient temperature and diluted with ethyl acetate and water. Theorganic layer was separated, dried over anhydrous sodium sulfate andconcentrated in vacuo. The crude was purified by flash chromatography(20% ethyl acetate/hexane) to provide tert-butyl(3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a viscous brown liquid (0.32, 45% yield): MS (ES) m/z 622.8 (M+H).

Step 2: Preparation ofN-((3R,5S)-5-methylpiperidin-3-yl)-5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A stirred solution of tert-butyl(3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.52 g, 1.00 mmol) in trifluoroacetic acid (5.0 mL) was heated at 100°C. for 1 hour in a sealed tube. The reaction mixture was cooled toambient temperature and then concentrated in vacuo, the residue wasdissolved in 1,4-dioxane:aqueous ammonia (5 mL:5 mL) and stirred atambient temperature for 16 hours. The reaction mixture was concentratedin vacuo to provideN-((3R,5S)-5-methylpiperidin-3-yl)-5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas a brown gummy solid (0.45 g, crude): MS (ES) m/z 392.1 (M+H).

Step 3: Preparation of3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

A solution of 2-cyanoacetic acid (0.13 g, 1.53 mmol),1-hydroxybenzotriazole (0.19 mg, 1.23 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.29 g,1.53 mmol) in dichloromethane (4.0 mL) was stirred at ambienttemperature for 3 minutes. ThenN-((3R,5S)-5-methylpiperidin-3-yl)-5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.40 g, 1.02 mmol) was added followed by triethylamine (0.70 mL, 5.11mmol) and the mixture stirred at ambient temperature overnight. Thereaction mixture was diluted with ethyl acetate, washed with water andbrine. The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude was purified by reversephase chromatography to provide3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas an off-white solid (0.05 g, 11% yield): ¹H NMR (400 MHz, DMSO-d₆, VTat 80° C.) δ 11.56 (br s, 1H), 9.33 (br s, 1H), 8.41 (s, 1H), 8.30 (s,1H), 7.21 (s, 1H), 6.76 (s, 1H), 4.79 (br s, 1H), 3.84-4.44 (m, 3H),3.60-3.74 (m, 1H), 3.56 (s, 1H), 3.39 (s, 3H), 2.60-2.80 (m, 1H),2.20-2.40 (m, 1H), 1.75-1.85 (m, 1H), 1.15-1.27 (m, 1H), 0.94 (d, J=6.4Hz, 3H); MS (ES) m/z 459.1 (M+H).

Analytical Conditions:

Mobile Phase A: 0.1% NH₄OH in H₂O

Mobile Phase B: MeCN

Column: X-Bridge, C18 19*100*5 micron

Flow rate: 20 mL/min

Example 66. Preparation of(R)-3-(3-((5-(5-acetyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-5-carboxylate

To a stirred solution of tert-butyl(3R)-3-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}piperidine-1-carboxylate(1.50 g, 2.62 mmol) and ethyl 2-bromo-1,3-oxazole-5-carboxylate (0.38 g,1.74 mmol) in 1,4-dioxane (40 mL) was addedbis(triphenylphosphine)palladium(II) dichloride (0.25 g, 0.35 mol) and2M aqueous solution of tripotassium phosphate (1.48 g, 6.97 mmol) andthe mixture stirred at 110° C. for 16 hours. The reaction was cooled toambient temperature, diluted with ethyl acetate, washed with water andbrine. The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude was purified using flashchromatography (20% ethyl acetate/hexane) to provide ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-5-carboxylateas a viscous brown liquid (0.65 g, 63% yield): MS (ES) m/z 586.3 (M+H).

Step 2: Preparation of(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-5-carboxylicacid

To a stirred solution of ethyl(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-5-carboxylate (0.50g, 0.85 mmol) in methanol (20 mL) was added 2M aqueous solution ofsodium hydroxide (0.17 g, 4.27 mmol) and the solution stirred at ambienttemperature for 4 hours. The reaction was concentrated to removevolatiles, the obtained residue was dissolved in water and acidifiedwith 1N hydrochloric acid and adjusted to pH˜3. The aqueous layer wasextracted with ethyl acetate, dried over anhydrous sodium sulfate,filtered and concentrated to provide(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-5-carboxylicacid as a colorless gum (0.22 g, 46% yield): MS (ES) m/z 558.3 (M+H).

Step 3: Preparation of tert-butyl(R)-3-((5-(5-(methoxy(methyl)carbamoyl)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A solution of(R)-2-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-5-carboxylicacid (0.22 g, 0.40 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (HATU) (0.23 g, 0.60 mmol) in N,N-dimethylformamide(5 mL) was stirred at ambient temperature for 3 minutes. ThenN,O-dimethylhydroxylamine hydrochloride (0.2 g, 1.2 mmol) was addedfollowed by triethylamine (0.38 mL, 2.76 mmol) and the mixture stirredat ambient temperature for 5 hours. The reaction mixture was quenchedwith water and extracted with ethyl acetate. The organic layer waswashed with water, brine, dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. The crude material was purified by flashchromatography (30% ethyl acetate/hexane) to provide tert-butyl(R)-3-((5-(5-(methoxy(methyl)carbamoyl)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a viscous liquid (0.2 g, 84% yield): MS (ES) m/z 601.6 (M+H).

Step 4: Preparation of tert-butyl(R)-3-((5-(5-acetyloxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a solution of tert-butyl(R)-3-((5-(5-(methoxy(methyl)carbamoyl)oxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.20 g, 0.33 mmol) in tetrahydrofuran (4.0 mL) at 0° C. was addedmethyl magnesium bromide (0.34 mL, 1.00 mmol). The reaction mixture waswarmed to ambient temperature and stirred for overnight. The reactionmixture was quenched with saturated ammonium chloride solution andextracted with ethyl acetate. The organic layer was washed with water,brine, dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The crude material was purified using flash chromatography (40%ethyl acetate/hexane) to provide tert-butyl(R)-3-((5-(5-acetyloxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a pale yellow semi solid (0.12 g, 65% yield): MS (ES) m/z 556.3(M+H).

Step 5: Preparation of(R)-1-(2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazol-5-yl)ethan-1-one

A solution of tert-butyl(R)-3-((5-(5-acetyloxazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.12 g, 0.22 mmol) in dichloromethane:trifluoroacetic acid (2.0 mL:2.0mL) was stirred at ambient temperature. After 3 hours the reaction wasconcentrated to dryness, the residue was dissolved in1,4-dioxane:aqueous ammonia (2 mL:2 mL) and stirred at ambienttemperature for 16 hours. The reaction mixture was concentrated in vacuoto provide(R)-1-(2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazol-5-yl)ethan-1-oneas a colorless gum (0.12 g, crude): MS (ES) m/z 326.3 (M+H).

Step 6: Preparation of(R)-3-(3-((5-(5-acetyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

To a stirred solution of 2-cyanoacetic acid (0.04 g, 0.42 mmol) and1-hydroxybenzotriazole (0.51 g, 0.33 mmol) in dichloromethane (5 mL) wasadded N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.8g, 0.42 mmol) and the mixture stirred at ambient temperature for 5minutes. Then(R)-1-(2-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazol-5-yl)ethan-1-one(0.09 g, 0.28 mmol) was added followed by triethylamine (0.2 mL, 0.38mmol) and the resulting mixture stirred at ambient temperature for 18hours. The reaction mixture was quenched with water and extracted withdichloromethane. The organic layer was washed with water, brine, driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Thecrude material was purified by reverse phase chromatography to provide(R)-3-(3-((5-(5-acetyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileas a pale yellow solid (7.0 mg, 7% yield): ¹H NMR (400 MHz, DMSO-d₆, VTat 80° C.) δ 11.53 (br s, 1H), 9.45 (br s, 1H), 8.61 (s, 1H), 8.11 (s,1H), 7.21 (s, 1H), 6.70 (s, 1H), 4.20-4.40 (m, 1H), 3.80-4.00 (m, 3H),3.50-3.65 (m, 1H), 3.40-3.50 (m, 3H), 2.00-2.15 (m, 2H), 1.55-1.84 (m,4H); MS (ES) m/z 393.1 (M+H).

Analytical Conditions:

Mobile Phase A: 0.1% NH₄OH in H₂O

Mobile Phase B: MeCN

Column: Phenomenex, C18, 21.2 mm*250 mm*5 micron,

Flow rate: 20 mL/min

Example 67. Preparation ofN-((3R,5S)-1-((2,2-difluorocyclopropyl)methyl)-5-methylpiperidin-3-yl)-5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

Step 1: Preparation of2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole

A stirred solution of5-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(1.5 g, 4.15 mmol), 2-(tributylstannyl)thiazole (1.7 g, 4.57 mmol) andbis(triphenylphosphine)palladium(II) dichloride (0.58 g, 0.83 mmol) inN-methyl-2-pyrrolidone (15 mL) was heated at 130° C. in a sealed tubeunder a nitrogen atmosphere. After 5 hours the reaction mixture wascooled to ambient temperature, diluted with ethyl acetate and filteredthrough celite. The filtrate was washed with water, brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by using flash chromatography (10% ethyl acetatein hexane) to provide2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazoleas a colorless oil (0.75 g, 49% yield): MS (ES) m/z 365.8 (M+H).

Step 2: Preparation of benzyl(3S,5R)-3-methyl-5-((5-(thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A stirred solution of2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole(1.0 g, 2.73 mmol), benzyl(3R,5S)-3-amino-5-methylpiperidine-1-carboxylate (0.74 g, 3.0 mmol) andN,N-diisopropylethylamine (2.0 mL, 13.6 mmol) in N-methyl-2-pyrrolidone(20 mL) was heated at 175° C. for 20 hours. The reaction was cooled toambient temperature, diluted with ethyl acetate, washed with water,brine, dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The crude material was purified by using flash chromatography(20% ethyl acetate in hexane) to provide benzyl(3S,5R)-3-methyl-5-((5-(thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a yellow liquid (0.5 g, 32% yield): MS (ES) m/z 578.9 (M+H).

Step 3: Preparation ofN-((3R,5S)-5-methylpiperidin-3-yl)-5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of benzyl(3S,5R)-3-methyl-5-((5-(thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(0.5 g, 0.39 mmol) and trifluoroacetic acid (5.0 mL) was stirred at 100°C. for 1 hour in a sealed tube. After cooling the reaction mixture wasconcentrated in vacuo, the obtained residue was dissolved in1,4-dioxane:aqueous ammonia (5.0 mL:5.0 mL) and stirred at ambienttemperature overnight. The reaction mixture was concentrated in vacuo toprovideN-((3R,5S)-5-methylpiperidin-3-yl)-5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas an off-white solid (0.2 g, crude): MS (ES) m/z 314.0 (M+H).

Step 4: Preparation ofN-((3R,5S)-1-((2,2-difluorocyclopropyl)methyl)-5-methylpiperidin-3-yl)-5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

To a stirred solution of(3R,5S)-5-methyl-N-[5-(1,3-thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-amine(0.1 g, 0.32 mmol) in N-methylpyrrolidin-2-one (1.5 mL) was added2-(bromomethyl)-1,1-difluorocyclopropane (0.87 g, 0.51 mmol) and thesolution heated at 70° C. for 12 hours in a sealed tube. After cooling,the reaction was quenched with ice cold water, extracted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude material was purifiedusing reverse phase to chromatography provideN-((3R,5S)-1-((2,2-difluorocyclopropyl)methyl)-5-methylpiperidin-3-yl)-5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.003 g, 3% yield) as an off-white solid: ¹H NMR (400 MHz, DMSO-d₆, VTat 80° C.) δ 11.35 (m, 1H), 9.53 (m, 1H), 8.37 (m, 1H), 7.80 (s, 1H),7.50 (s, 1H), 7.15 (m, 1H), 6.55 (m, 1H), 4.21 (m, 1H), 3.3 (m, 1H),2.80-2.92 (m, 1H), 2.17-2.31 (m, 1H), 1.73-1.92 (m, 3H), 1.42-1.59 (m,1H), 1.35 (m, 1H), 1.24 (s, 3H), 0.90-1.11 (m, 4H); MS (ES) m/z 404.3(M+H).

Analytical Conditions:

Column: Sunfire C18 19*150*5 micron

Mobile phase(A): 0.1% TFA in H₂O

Mobile phase(B): MeCN

Flow rate: 20 mL/min

Example 68. Preparation of3-((3R,5S)-3-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile

Step 1: Preparation of ethyl4-(((3R,5S)-1-((benzyloxy)carbonyl)-5-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a stirred solution of ethyl4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(1.0 g, 2.82 mmol) in N-methyl-2-pyrrolidone (15 mL) was added benzyl(3R,5S)-3-amino-5-methylpiperidine-1-carboxylate (0.84 g, 3.38 mmol)followed by N,N-diisopropylethylamine (1.0 mL) and the mixture washeated to 180° C. for 18 hours in a sealed tube. The reaction mixturewas cooled to ambient temperature, quenched with water and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by flash chromatography (20% ethyl acetate/hexane)to provide ethyl4-(((3R,5S)-1-((benzyloxy)carbonyl)-5-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylateas a colorless oil (0.85 g, 53% yield): MS (ES) m/z 567.3 [M+H]⁺.

Step 2: Preparation of4-(((3R,5S)-1-((benzyloxy)carbonyl)-5-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid

To a stirred solution of ethyl4-(((3R,5S)-1-((benzyloxy)carbonyl)-5-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(0.85 g, 1.50 mmol) in methanol (10 mL) was added 2M aqueous solution oflithium hydroxide-monohydrate (0.126 g, 3.0 mmol) and the solutionstirred at room temperature for 6 hours at 50° C. for 2 hours. Thereaction was cooled to ambient temperature and concentrated in vacuo toremove volatiles. The residue was dissolved in water and acidified with1N hydrochloric acid to adjust pH-3. The aqueous layer was extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudematerial was triturated with n-pentane to provide4-(((3R,5S)-1-((benzyloxy)carbonyl)-5-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid as a sticky solid (0.7 g, crude): MS (ES) m/z 539.3 [M+H]⁺.

Step 3: Preparation of benzyl(3R,5S)-3-((5-(2-formylhydrazine-1-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidine-1-carboxylate

A solution of4-(((3R,5S)-1-((benzyloxy)carbonyl)-5-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.6 g, 1.11mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (0.50 g, 1.34 mmol) in dimethylformamide (10 mL) wasstirred at ambient temperature for 3 minutes. Formylhydrazide (0.13 g,2.23 mmol) was added followed by N,N-diisopropylethylamine (0.6 mL, 3.34mmol) and the mixture stirred at ambient temperature for 3 hours. Thereaction was quenched with water and extracted with ethyl acetate. Theorganic layer was washed with brine and dried over anhydrous sodiumsulfate. The solution was filtered and concentrated in vacuo to providebenzyl(3R,5S)-3-((5-(2-formylhydrazine-1-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidine-1-carboxylateas an off-white solid (0.45 g, 69% yield): MS (ES) m/z 581.3 [M+H]⁺.

Step 4: Preparation of benzyl(3R,5S)-3-((5-(1,3,4-thiadiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidine-1-carboxylate

To a solution of benzyl(3R,5S)-3-((5-(2-formylhydrazine-1-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidine-1-carboxylate(0.45 g, 0.77 mmol) in tetrahydrofuran (20 mL) was added Lawesson'sreagent (0.47 g, 1.16 mmol) at ambient temperature and the mixturestirred at 70° C. for 16 hours. The reaction was cooled to ambienttemperature and quenched with saturated sodium bicarbonate solution. Theproduct was extracted with ethyl acetate, the organic layer washed withwater and brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (30% ethyl acetate/hexane) to provide benzyl(3R,5S)-3-((5-(1,3,4-thiadiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidine-1-carboxylateas an off white solid (0.35 g, 78% yield): MS (ES) m/z 579.3 [M+H]⁺.

Step 5: Preparation ofN-((3R,5S)-5-methylpiperidin-3-yl)-5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

A solution of benzyl(3R,5S)-3-((5-(1,3,4-thiadiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidine-1-carboxylate(0.35 g, 1.02 mmol) and trifluoroacetic acid (5.0 mL) was stirred at100° C. for 1 hour in a sealed tube. After cooling the reaction mixturewas concentrated in vacuo, the obtained residue was dissolved in1,4-dioxane:aqueous ammonia (5.0 mL:5.0 mL) and stirred at ambienttemperature overnight. The reaction mixture was concentrated in vacuo toprovideN-((3R,5S)-5-methylpiperidin-3-yl)-5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amineas an off-white solid (0.3 g, crude): MS (ES) m/z 315.2 (M+H).

Step 6: Preparation of3-((3R,5S)-3-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile

A solution of 2-cyanoacetic acid (0.16 g, 1.91 mmol),1-hydroxybenzotriazole (0.22 g, 1.43 mmol) and1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.27 g,1.43 mmol) in N,N-dimethylformamide (6 mL) was stirred at ambienttemperature for 3 minutes, ThenN-((3R,5S)-5-methylpiperidin-3-yl)-5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine(0.3 g, 0.95 mmol) was added followed by N,N-diisopropylethylamine (0.5mL, 2.86 mmol) and the resulting mixture stirred at ambient temperaturefor 3 hours. The reaction mixture was quenched with ice cold water andthe product extracted with ethyl acetate. The organic layer was washedwith sodium bicarbonate solution, brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The crude material waspurified using reverse phase chromatography to provide3-((3R,5S)-3-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrileas an off white solid (0.02 g, 5% yield): ¹H NMR (400 MHz, DMSO-d₆) δ11.71 (br s, 1H), 9.36-9.46 (m, 2H), 8.34 (s, 1H), 7.25 (s, 1H), 6.79(s, 1H), 4.82-4.84 (m, 1H), 4.30 (m, 1H), 3.93-4.09 (m, 3H), 3.58-3.61(m, 1H), 2.64-2.74 (m, 1H), 2.19-2.30 (m, 1H), 1.87 (m, 1H), 1.32-1.35(m, 1H), 0.91 (br s, 3H); MS (ES) m/z 382.4 (M+H).

Analytical Conditions:

Column: X-Bridge, C18 19*100*5 micron

Mobile phase(A): 0.1% Ammonium hydroxide in water

Mobile phase(B): MeCN

Flow rate: 20 mL/min

Preparation of tert-butyl(R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

Step 1: Preparation of5-bromo-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To a stirred solution of 5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (20g, 87.3 mmol), triethylamine (36.4 mL, 262.0 mmol) and4-dimethylaminopyridine (1.06 g, 8.73 mmol) in dichloromethane (40 mL)was added p-toulenesufonyl chloride (24.9 g, 131.0 mmol) at 0° C. andthe mixture stirred at room temperature for 1 hour. The reaction wasquenched with water and extracted with ethyl acetate. The organic layerwas washed with water, brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude product was washed withn-hexane to provide 5-bromo-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridineas an off-white solid (32.5 g, 97% yield): MS (ES) m/z 387.0 (M+2).

Step 2: Preparation of tert-butyl(R)-3-((5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

In a sealed tube a stirred solution of5-bromo-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (5 g, 13.0 mmol),tert-butyl (R)-3-aminopiperidine-1-carboxylate (3.9 g, 19.5 mmol) andtriethylamine (0.9 mL, 6.5 mmol) in N-methylpyrrolidone (25 mL) washeated at 150° C. for 16 h. The reaction was cooled to ambienttemperature and the reaction was quenched with water and extracted withethyl acetate. The organic layer was washed with water, brine, driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Thecrude material was purified using flash chromatography (15% ethylacetate/hexane) to provide tert-butyl(R)-3-((5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a brown liquid (4.0 g, 56% yield): MS (ES) m/z 549 (M+).

Step 3: Preparation of tert-butyl(R)-3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

A stirred solution of tert-butyl(R)-3-((5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(18.4 g, 33.5 mmol) and lithium hydroxide monohydrate (4.93 g, 117.5mmol) in THF:MeOH:water (25 mL:100 mL:25 mL) was heated to 60° C. for 2hours. The reaction was cooled to ambient temperature and thenconcentrated in vacuo. The crude was dissolved in ethyl acetate andwashed with water, brine, dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to provide tert-butyl(R)-3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a brown liquid (12.4 g, crude): MS (ES) m/z 395.1 (M+).

Step 4: Preparation of tert-butyl(R)-3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a suspension of sodium hydride (1.29 g, 32.4 mmol, 60% suspension inmineral oil) in dry dimethylformamide (80 mL) was slowly addedtert-butyl(R)-3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(8.0 g, 20.2 mmol) at 0° C. and the mixture stirred for 30 minutes. Then2-(trimethylsilyl)ethoxymethyl chloride (6.45 mL, 36.4 mmol) was addedat 0° C. and the mixture stirred at ambient temperature for 1.5 hours.The reaction mixture was quenched with saturated ammonium chloridesolution and extracted with ethyl acetate. The organic extract waswashed with water, brine, and dried over anhydrous sodium sulfate. Thesolution was filtered and concentrated in vacuo to provide a crudematerial which was purified by column chromatography (5% ethylacetate/hexane) to provide tert-butyl(R)-3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a yellow oil (7.0 g, 66% yield): MS (ES) m/z 525.0 (M+).

Step 5: Preparation of tert-butyl(R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate

To a solution of tert-butyl(R)-3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate(2 g, 3.80 mmol) in 1,4-dioxane:toluene (4:1) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.25 g,4.95 mmol) and potassium phosphate tribasic (2.42 g, 11.4 mmol). Themixture was purged with nitrogen for 15 minutes. X-Phos Pd G2 (0.60 g,0.76 mmol) was added and the resulting mixture stirred at 110° C. for 15minutes on pre-heated oil bath. The reaction was cooled to ambienttemperature, diluted with ethyl acetate and filtered through celite. Thefiltrate was washed with water, brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to provide tert-butyl(R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylateas a crude (3 g, crude): MS (ES) m/z 573.0 (M+H)⁺.

Biological Activity Assay JAK1, JAK2, JAK3, and Tyk-2 Enzyme ActivityAssays

The activity of JAK3 (a.a. 781-1124, ThermoFisher) was quantified bymeasuring the phosphorylation of SRCtide (FAM-GEEPLYWSFPAKKK-NH₂).Kinase reactions were run in a 384-well Greiner plate with 2% final DMSOconcentration under the buffer conditions of 20 mM HEPES, pH 7.5, 10 mMMgCl₂, 0.01% BSA, and 0.0005% Tween-20. The kinase reaction componentswere 2.5 nM JAK3, 1 μM SRCtide peptide and 1 uM ATP. Examples weretested in dose-response starting at 2 μM (11 concentrations, 3-foldserial dilution, duplicate reactions). The reactions were incubated atroom temperature for 40 minutes, then stopped by adding a 1:1 volume of30 mM EDTA in 20 mM HEPES, pH 7.5 (15 mM EDTA final). After the reactionwas stopped, the phosphorylated and unphosphorylated peptides wereseparated and quantified using a Caliper LC3000/EZ-Reader system and HTSWell Analyzer Software (Caliper, A PerkinElmer Company, Hopkinton,Mass.). GraFit (Erithacus Software Ltd., Horley, U.K.) was used tocalculate inhibitor potency by fitting dose-response data to the4-parameter logistical IC₅₀ equation.

The inhibitory potency of candidate compounds of JAK1, JAK2, and Tyk-2was done at Thermo Fisher Scientific in their Selectscreen using aZ-lyte assay. Following are the assay details for each enzyme.

JAK1: The 2×JAK-enzyme/Tyr 06 mixture is prepared in 50 mM HEPES pH 6.5,0.01% BRIJ-35, 10 mM MgCl₂, 1 mM EGTA, 0.02% NaN₃. The final 10 μL ofthe Kinase Reaction consists of 21.2-91.5 ng JAK1 and 2 μM Tyr 06 in 50mM HEPES pH 7.0, 0.01% BRIJ-35, 10 mM MgCl₂, 1 mM EGTA, 0.01% NaN₃.After the one hour Kinase Reaction incubation, 5 μL of a 1:128 dilutionof Development Reagent is added.

JAK2: The 2×JAK2/Tyr 06 mixture is prepared in 50 mM HEPES pH 7.5, 0.01%BRIJ-35, 10 mM MgCl₂, 1 mM EGTA. The final 10 μL Kinase Reactionconsists of 0.12-0.5 ng JAK2 and 2 μM Tyr 06 in 50 mM HEPES pH 7.5,0.01% BRIJ-35, 10 mM MgCl₂, 1 mM EGTA. After the one hour KinaseReaction incubation, 5 μL of a 1:128 dilution of Development Reagent Ais added.

TYK2: The 2×TYK2/Tyr 03 mixture is prepared in 50 mM HEPES pH 6.5, 0.01%BRIJ-35, 10 mM MgCl₂, 1 mM EGTA, 0.02% NaN₃. The final 10 μL KinaseReaction consists of 3.75-15 ng TYK2 and 2 μM Tyr 03 in 50 mM HEPES pH7.0, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA, 0.01% NaN₃. After the onehour KinaseReaction incubation, 5 μL of a 1:4096 dilution of DevelopmentReagent A is added.

Data reduction for JAK1, JAK2 and TYK2 is done the same, independent ofthe enzyme run. In summary, background signal is defined in the absenceof enzyme and uninhibited signal is defined in the presence of vehicle(2% DMSO) alone. Compounds were evaluated in an 11 point dose-responseranging from 20 mM to 0.34 nM. IC₅₀ values of compounds are determinedusing a 4 parameter logistical fit of emission ratio as a function ofthe concentration of compound. The results are shown in Table 3.

TABLE 3 JAK1 JAK2 JAK3 Tyk-2 Inhibition Inhibition Inhibition InhibitionIC₅₀ IC₅₀ IC₅₀ IC₅₀ +++indicates +++indicates +++indicates +++indicates≤0.01 μM ≤0.01 μM ≤0.01 μM ≤0.01 μM ++indicates ++indicates ++indicates++indicates 0.01-0.1 μM 0.01-0.1 μM 0.01-0.1 μM 0.01-0.1 μM +indicates+indicates +indicates +indicates 0.1-1 μM 0.1-1 μM 0.1-1 μM 0.1-1 μMExample −indicates −indicates −indicates −indicates No >l μM >l μM >lμM >l μM  1 ++ ++ ++ ++  2 +++ ++ +++ ++  3 ++ + ++ +  4 +++ +++ +++ +++ 5 +++ +++ +++ +++  6 +++ ++ +++ ++  7 ++ ++ ++ ++  8 +++ ++ +++ ++ 9 + + ++ + 10 +++ +++ +++ +++ 11 ++ ++ ++ + 12 + + ++ + 13 ++ ++ ++ +14 +++ ++ +++ ++ 15 +++ ++ +++ ++ 16 ++ + ++ + 17 − − − − 18 +++ ++ +++++ 19 ++ + ++ + 20 +++ ++ ++ + 21 +++ ++ ++ ++ 22 ++ ++ ++ ++ 23 ++ +++ + 24 +++ ++ +++ +++ 25 +++ ++ ++ ++ 26 +++ ++ ++ ++ 27 ++ ++ +++ + 28+++ +++ +++ +++ 29 ++ ++ +++ + 30 +++ +++ + +++ 31 +++ +++ +++ +++32 + + ++ + 33 +++ ++ +++ ++ 34 +++ ++ +++ ++ 35 +++ ++ +++ ++ 36 ++++++ +++ +++ 37 +++ ++ +++ ++ 38 ++ ++ ++ + 39 ++ +++ +++ ++ 40 +++ ++++++ +++ 41 +++ +++ +++ +++ 42 +++ +++ +++ +++ 43 +++ ++ ++ ++ 44 +++ ++++ ++ 45 +++ +++ +++ +++ 46 +++ +++ +++ +++ 47 ++ ++ ++ ++ 48 +++ ++ ++++ 49 +++ ++ +++ ++ 50 +++ ++ +++ ++ 51 +++ +++ +++ ++ 52 +++ +++ ++++++ 53 +++ +++ +++ +++ 54 ++ ++ + + 55 +++ ++ +++ +++ 56 ++ + + + 57 + +++ + 58 +++ + ++ + 59 +++ + + − 60 +++ ++ ++ ++ 61 ++ ++ ++ + 62 +++ ++++++ ++ 63 +++ +++ +++ ++ 64 +++ +++ +++ +++ 65 +++ +++ +++ +++ 66 +++ +++++ ++ 67 ++ ++ +++ ++ 68 +++ +++ +++ +++

JAK Cellular Target Modulation Assays

Target modulation was based upon the ability of a compound to inhibitJAK isoform specific phosphorylation of selected substrates. IL-2stimulated STAT5 phosphorylation on Tyr694 was used to assess JAK1/3compound selectivity. GM-CSF stimulated STAT5 phosphorylation on Tyr694was used to assess JAK2 compound selectivity. IFNγ stimulated STAT1phosphorylation on Tyr701 was used to assess JAK1/2 compoundselectivity. IL-12 stimulated STAT4 phosphorylation on Tyr693 was usedto assess JAK2/TYK2 compound selectivity. For all four assays, humanPBMC from frozen stocks were thawed, pelleted, resuspended in completemedia (90% RPMI, 10% heat inactivated FBS, 10 mM HEPES, 47 μM 2-ME,pen/strep) and placed in wells of a 96 well V-bottom plate at 200,000per well in 120 μl complete media. Compounds were added as 15 μl perwell of 10× working stock solutions in complete media with 1% DMSO (ormedium with 1% DMSO for controls) and placed on a plate shaker in a 37°C. incubator with 5% CO₂ for 1 hour with gentle shaking (setting of 3).Stimulation used the addition of soluble cytokines. For the JAK1/3phospho-STAT5 assay, 15 μl of 10× working stock recombinant human IL-2was added to a final concentration of 25 ng/ml. For the JAK2phospho-STAT5 assay, 15 μl of 10× working stock recombinant human GM-CSFwas added to a final concentration of 5 ng/ml. For the JAK1/2phospho-STAT1 assay, 15 μl of 10× working stock of recombinant humanIFNγ was added to a final concentration of 10 ng/ml. For the JAK2/TYK2phospho-STAT4 assay, 15 μl of 10× working stock of recombinant humanIL-12 was added to a final concentration of 1.7 ng/ml. Plates were thenplaced back on the plate shaker in the incubator for an additional 5, 5,10, and 25 minutes respectively upon which the plates were removed fromthe incubator, sealed with a plate sealer and the cells pelleted at400×g for 5 minutes. After pelleting, the media was removed byaspiration and the cells were lysed in assay specific cell lysis buffer.The levels of phospho-STAT5 were determined using a Phospho(Tyr694)STAT5a,b Whole Cell Lysate kit from Meso Scale Discovery. Levelsof phospho-STAT1 were determined using a CST-PathScan Phospho-STAT1(Tyr701) Sandwich ELISA kit. Levels of phospho-STAT4 were determinedusing a Phospho-STAT4 (Tyr693) Whole Cell Lysate kit from Meso ScaleDiscovery. The results are shown in Table 4.

TABLE 4 IL2-STAT5 IC₅₀ Infγ-STAT1 IC₅₀ IL12-STAT4 IC₅₀ ++indicates ≤0.1++indicates ≤0.1 ++indicates ≤0.1 μM +indicates μM +indicates μM+indicates Example 0.1-1 μM 0.1-1 μM 0.1-1 μM No −indicates >l μM−indicates >l μM −indicates >l μM  1 + +  2 ++ + +  3 + −  4 ++ ++ +  5++ ++ +  6 ++ + −  7 + + −  8 ++ + +  9 − 10 ++ ++ ++ 11 − − 12 + − 13 +− − 14 + − 15 ++ + − 16 + − 17 − 18 ++ + − 19 + − − 20 ++ + − 21 ++ + +22 + + − 23 + − − 24 ++ + + 25 ++ + 26 ++ + − 27 + − − 28 ++ ++ + 29++ + − 30 + + − 31 ++ ++ − 32 − 33 ++ + − 34 + + − 35 + − 36 ++ ++ + 37++ + − 38 + − − 39 − − 40 ++ ++ ++ 41 ++ + + 42 ++ + + 43 ++ + − 44 + +− 45 + + − 46 ++ ++ + 47 + − − 48 ++ + − 49 ++ ++ − 50 − 51 + + − 52 ++++ + 53 ++ ++ 54 − 55 ++ + − 56 − 57 − 58 + − 59 + − 60 ++ + − 61 − 62++ + − 63 ++ + − 64 ++ ++ − 65 ++ ++ ++ 66 ++ + 67 + + − 68 ++ ++ ++

GI Exposure PK in Mice

The test compound was wetted with ˜0.025% of Tween-20 and triturated ina mortar and pestle, then slowly 0.500 of methyl cellulose was added tomake up the final volume to 7.25 mL. The BalbC test animals weresubjected to anesthesia induced with a mixture of 500 isoflurane and0.8-1.5 L/min O₂ gas flow. The formulated test compound was then dosedvia oral gavage. At various time points (0.5, 1, 2, 4, 6 and 8 h) bloodsamples (˜100 μL) were collected from portal vein (pre-hepatic) followedby cardiac puncture (circulating) into tubes containing 2% w/v aqueousK₂ EDTA solution as per time points. Post blood sampling, the gastrointestine (GI) tissues were collected from the mice at the same timepoints. The GI tissue was dissected into different parts as duodenum,jejunum, ileum and colon. The separated tissues were washed by flushingwith PBS via oral gavage needle to remove GI content. Post collectionall the tissues were blotted, weighed and homogenized with PBS buffer(pH 7.4). The blood samples were immediately placed on ice andcentrifuged within 30 min at 4° C. for 5 min at 8,000 rpm to obtainplasma. Plasma was transferred by pipettes to pre-labelled centrifugetubes and immediately transferred to −80° C. until bioanalysis. Tissuesamples were placed in pre-labelled container and all samples were keptin −80° C. until homogenized. The homogenate was stored immediately in−80° C. until bioanalysis was conducted. Study samples were thawed toroom temperature and 50 μL of sample was aliquoted into pre-labeledvials. To these was added 400 μL of 100% acetonitrile containing an IS(100 ng/mL; warfarin, tolbutamide and loperamide). The vials were mixedwell, vortexed for 5 min, followed by centrifugation for 5 min at 14000rpm at 4° C. The supernatant was separated and same was injected onLC-MS/MS. Plasma and GI tissue levels of test compound were determinedby LC-MS analysis using a standard curve in the text matrix. Individualconcentration-time data were analyzed using Phoenix WinNonlin (Version8.1) by the non-compartmental analysis (NCA) method. The results areshown in Table 5.

TABLE 5 Cmax, Tmax, and AUC calculations for Example 31 in male BalbCmice after an oral dose of 5 mg/kg. Cmax Tmax AUC Tissue (ng/mL or ng/g)(h) h*ng/mL Circulating plasma 9.2¹ 4 NRV² Portal plasma 11.3 0.5 17.2Duodenum 2881 0.5 4658 Jejunum 37007 0.5 57391 Ileum 43840 2 82490 Colon1286 4 6815 ¹For two of three subjects, below limit of quatification(BLQ) for third animal. Other time points are BLQ except at 8 h for oneanimal with 13.5 ng/mL. ²NRV (No reported value)-Insufficient datapoints to calculate the PK parameter.

Acute DSS Colitis Model in Mice

Oral administration of the sulfated polysaccharide dextran sulfatesodium (DSS) to mice via drinking water induces severe colitischaracterized by weight loss, bloody diarrhea, ulcer formation, loss ofepithelial cells and infiltrations with neutrophils, macrophages andlymphocytes, resembling some features of human inflammatory boweldisease (IBD). See Okayasu, I. et al. Gastroenterology, 98: 694-702(1990) and Wirtz et al. Nature Protocols. 12(7):1295 (2017).Nine-twelve-week old female C57BL/6 mice from Charles River were given4% DSS (Colitis grade DSS, molecular weight: 36,000-50,000; MPBiomedicals Cat. No. 160110) in sterile drinking water for 5 days. Onday 6, the mice were switched to sterile drinking water, and drugs weredosed (PO, BID) from day 6 to 10 or day 10 to 14.

Body weight was monitored daily and reported as a percentage of initialbody weight. Stool consistency and bloody diarrhea were also scored(0-4). At the end of each study, mice were sacrificed and the entirecolon was removed and flushed with PBS. The colon weight and length weremeasured, and the ratio of colon weight to length was reported. A 0.5 cmsegment of the distal colon was collected in a microfuge tube and frozenin dry ice. Lysates of this tissue were prepared for colonic cytokinedetermination using V-PLEX mouse cytokine 29-plex kit from MSD. A 3 cmsegment of distal colon was collected to a cassette and fixed in 10%formalin for histology. Slides were prepared and stained withhematoxylin and eosin (H&E) and scored in a blinded fashion by apathologist. Scoring of H&E slides included categories for inflammation,gland loss, erosion, submucosal edema, mucosal thickness, neutrophilscore and lymphoid aggregate count and size.

All references, patents or applications, U.S. or foreign, cited in theapplication are hereby incorporated by reference as if written herein intheir entireties. Where any inconsistencies arise, material literallydisclosed herein controls.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A method of treating a JAK-mediated disease in a subject in needthereof, said method comprising: administering, to a subject having theJAK-mediated disease, a compound, a derivative thereof, or a combinationthereof, of Formula (I):

wherein: R₁ is selected from CN or a heteroaryl group and is optionallysubstituted at the one or more available nitrogen atoms with a groupindependently selected from H or C₁-C₅alkyl and at one or more availablecarbon atoms with substituents wherein each substituent is independentlyselected from H, halogen, CN, —C₁-C₄alkyl, —C₀-C₆alkylC₃-C₆cycloalkyl,—(C₀-C₆alkyl)C₃-C₆heterocycle, —OH, —SO₂R₉, —SOR₉, —SR₉, —NHSO₂R₉,—OSO₂R₉, —C₀-C₆alkylSO₂R₉, C₀-C₆alkylCOR₉, C₀-C₆alkylNR₇C(O)NR₇R₈,C₀-C₆alkylOC(O)NR₇R₈, C₀-C₆alkylNR₇SO₂R₉,—C₀-C₆alkylNR₇COR₉—OC₁-C₆alkyl, —OC₀-C₆alkylC₃-C₆cycloalkyl,—OC₀-C₆alkylC₃-C₆heterocycle, —OC₀-C₆alkylNR₇C(O)NR₇R₈,—OC₀-C₆alkylOC(O)NR₇R₈, —OC₀-C₆alkylNR₇SO₂R₉, —OC₀-C₆alkylNR₇COR₉,—NR₇R₈, —NR₇C₀-C₆alkylC₁-C₆alkyl, —NR₇C₀-C₆alkylC₃-C₆cycloalkyl,—NR₇C₀-C₆alkylNR₇C(O)NR₇R₈, —NR₇C₀-C₆alkylOC(O)NR₇R₈,—NR₇C₀-C₆alkylNR₇SO₂R₉, —NR₇C₀-C₆alkylNR₇COR₉,—NR₇C₀-C₆alkylC₃-C₆heterocycle, aryl and heteroaryl wherein each alkyl,cycloalkyl, aryl, heterocyclyl, or heteroaryl group is optionallysubstituted with one or more groups selected from: halogen, —OH,—C₀-C₆alkylNR₇R₈, —C₀-C₆alkylOH, —SO₂R₉, —SOR₉, —NHSO₂R₉,—C₀-C₆alkylNR₇R₄, CN, —C₁-C₅alkylalkoxy, C₁-C₅alkoxy or —O—C₁-C₅alkyl;R₂ is selected from H, —C₁-C₄alkyl, —C₃-C₆cycloalkyl, or—C₁-C₂alkyl-C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl groups areoptionally substituted with one or more groups selected from halogen,—OH, or —O—C₁-C₅alkyl; n is 2; Ring A is substituted at one or morecarbons with one, two, or three R₃ substituents wherein each R₃substituent is independently selected from H, halogen, —C₁-C₄alkyl,—C₃-C₆cycloalkyl, —OH, or —O—C₁-C₅alkyl wherein each alkyl or cycloalkylgroup is optionally substituted with one or more groups selected from:halogen, —OH, —C₁-C₅alkylalkoxy, or —O—C₁-C₅alkyl; Two R₃ groups on thesame or different carbon atoms of the ring A may be optionally joined toform a spirocyclic or bicyclic ring system with ring A; R₄ is selectedfrom —C(O)—R₆, —CH₂R₆, —C(O)—C₁-C₅alkyl, or —C(O)—C₃-C₆cycloalkyl,wherein the alkyl or cycloalkyl groups may be optionally substitutedwith one or more groups selected from —OH, halogen, alkyne, or —CN; R₅is selected from —C₁-C₅alkyl, or —C₃-C₆cycloalkyl wherein the alkyl orcycloalkyl groups may be optionally substituted by one or more groupsselected from halogen, —OH, or —O—C₁-C₅alkyl; R₆ is selected from—C₁-C₅alkyl, —C₃-C₆cycloalkyl, —C₁-C₅alkyl-C₃-C₆cycloalkyl, —NR₇R₈,—O-aryl, —O-heteroaryl, aryl, or heteroaryl wherein the alkyl,cycloalkyl, aryl or heteroaryl groups can be optionally substituted byone or more groups selected from halogen, —CN, alkyne, —OH,trifluoromethyl, —O—C₁-C₅alkyl, or —O—C₃-C₆cycloalkyl; R₇ and R₈ areindependently selected from H, —C₁-C₅ alkyl, —C₁-C₅ alkoxy, or —C₃-C₅cycloalkyl wherein the alkyl groups may be optionally substituted by oneor more groups selected from halogen, —OH, or —CN; R₇ and R₈ may beoptionally joined to form a ring to form a heterocycle such aspiperidine, pyrrolidine, or with another heteroatom to form a ring suchas morpholine wherein the heterocyclic ring may be optionallysubstituted by one or more groups selected from halogen, —OH, NH₂, NHMe,NMe₂, or —CN; and R₉ is selected from H, —C₁-C₅alkyl, —OC₁-C₅alkyl,—C₃-C₆cycloalkyl, and NR₇R₈ wherein the alkyl, heterocycle, orcycloalkyl groups may be optionally substituted by one or more groupsselected from halogen, —OH, NH₂, NHMe, NMe₂, or —CN; in an amounteffective to treat the JAK-mediated disease.
 2. The method of claim 1,wherein the compound is selected from the group consisting of:(R)-3-oxo-3-(3-((5-(thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,

(R)-3-(3-((5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

(R)-3-(3-((5-(2-methylthiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-oxo-3-(3-((5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,

(R)-3-(3-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3((5-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

rac-(R)-3-(3-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(4H-1,2,4-triazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide,

(R)-3-(3-((5-(4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-oxo-3-(3-((5-(thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,

(R)-3-(3-((5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(6-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-oxo-3-(3-((5-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,

(R)-3-(3-((5-(5-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-oxo-3-(3-((5-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,

(R)-3-oxo-3-(3-((5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,

(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile,

(R)-3-(3-((5-(3-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((2S,5R)-2-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) piperidin-1-yl)-3-oxopropanenitrile,

2-(4-(((3R,6S)-1-(2-cyanoacetyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide,

2-(4-(((3R,5S)-1-(2-cyanoacetyl)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide,

2-(4-(((3S,5R)-1-(2-cyanoacetyl)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide,

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide,

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethyl-oxazole-4-carboxamide,

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylthiazole-4-carboxamide,

(R)-3-(3-((5-(5-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3((5-(5-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,

(R)-3-(3-((5-(1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-5-carboxamide,

3-((3R,5S)-3-((5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile

(R)-3-(3-((5-(1-isothiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate,

(R)-3-(3-((5(5-(2-methoxypyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(6-aminopyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3R)-3-((5-(5-(methylsulfinyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,

(R)-3-(3-((5-(5-(methylsulfonyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(2-(methylthio)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

2-cyano-N-(1-(4-(4-(((R)-1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)pyrrolidin-3-yl)-N-methylacetamide,

(R)-3-(3-((5-(2-aminopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(2-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylthiazole-5-carboxamide,

(R)—N-(2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-4-yl)N,N-dimethylsulfuric diamide,

(R)-3-(3-((5-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)—N-(2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-4-yl)methanesulfonamide,

3-((3R,5S)-3-methyl-5-((5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(3-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylisonicotinamide,

(R)-3-(3-((5-(1-(2-hydroxyethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(3-(hydroxymethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(6-(hydroxymethyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(5-acetyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

N-((3R,5S)-1-((2,2-difluorocyclopropyl)methyl)-5-methylpiperidin-3-yl)-5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine,

3-((3R,5S)-3-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(5-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-(hydroxymethyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-(2-hydroxypropan-2-yl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-(fluoromethyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-acetyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(4-acetyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(4-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(4-(methylsulfonyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(4-(methylsulfonyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(5-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,

3-((3S,5R)-3-methyl-5-((5-(4-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,

3-((3R,5S)-3-((5-(4,5-bis(hydroxymethyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-(hydroxymethyl)-4-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-(hydroxymethyl)isoxazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-(2-hydroxypropan-2-yl)-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-(fluoromethyl)-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,

3-((3R,5S)-3-((5-(5-acetyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(5-methylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-(hydroxymethyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-(2-hydroxypropan-2-yl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-(fluoromethyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-acetylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(4-methylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(5-methylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,

3-((3S,5R)-3-methyl-5-((5-(4-methylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,

3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,

(R)-3-(3-((5-(5-acetylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3R,4R)-4-methyl-3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)isothiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-(2-hydroxypropan-2-yl)-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-(fluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-acetyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,

3-((2S,5R)-2-methyl-5-((5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((2S,5R)-5-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-2-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,4R)-4-methyl-3-((5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3R,4R)-3-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(5-(1-fluorocyclopropyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

N-((3R,5S)-5-methyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine,

3-((3S,5R)-3-methyl-5-((5-(3-methyl-1,2,4-thiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(6-acetylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(4-(methylsulfonyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(4-acetylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(6-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(4-(hydroxymethyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(2-(hydroxymethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(2-(fluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(2-methoxypyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

3-((3R,5S)-3-((5-(2-acetylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,

(R)-3-(3-((5-(4-(methylsulfonyl)pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(4-(methylsulfonyl)pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,

3-((3S,5R)-3-methyl-5-((5-(6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,and

3-((3R,5S)-3-((5-(6-(hydroxymethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile.


3. The method of claim 2 wherein the compound israc-(R)-3-(3-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile.


4. The method of claim 2 wherein the compound is2-(4-(((3R,5S)-1-(2-cyanoacetyl)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide.


5. The method of claim 2 wherein the compound is(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylthiazole-5-carboxamide.


6. The method of claim 2 wherein the compound is3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile.


7. The method of claim 2 wherein the compound is3-((3R,5S)-3-((5-(5-acetyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile.


8. The method of claim 2 wherein the compound is3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile.


9. The method of claim 2 wherein the compound is3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile


10. The method of claim 1 further comprising: administering anothertherapeutic agent.
 11. The method of claim 1, wherein said JAK-mediateddisease is selected from the group consisting of an autoimmune disordersor responses, broad activation of the immune responses, bacterialinfection, viral infection, inflammation, a chronic and/or acuteinflammatory disorder or condition, and/or auto-inflammatory disorder,fibrotic disorders, metabolic disorders, a neoplasm, or cardiovascularor cerebrovascular disorders, a skin disorder, pruritus, a hair lossdisorder, a cancer or malignancy, autoimmune connective tissue diseasesand an autoimmune condition; Still's disease, adult-onset Still'sdisease, Th17-associated inflammation, polychondritis (e.g. relapsingpolychondritis); myositis, polymyositis, autoimmune myositis,dermatomyositis, juvenile dermatomyositis; myasthenia gravis; Arthritis(e.g. rheumatoid arthritis, juvenile rheumatoid arthritis,systemic-onset juvenile rheumatoid arthritis, osteoarthritis, infectiousarthritis, inflammatory arthritis, inflammatory bowel disease-associatedarthritis, idiopathic arthritis, juvenile idiopathic arthritis, systemicjuvenile idiopathic arthritis, psoriatic arthritis),spondylitis/spondyloarthritis/spondyloarthropathy (ankylosingspondylitis), gout, scleroderma (systemic scleroderma, juvenilescleroderma), Reiter's syndrome/reactive arthritis, Lyme disease,lupus/systemic lupus erythematosus (SLE) (lupus erythematosus, pediatricsystemic lupus erythematosus, cutaneous lupus (subacute cutaneous lupus,chronic cutaneous lupus/discoid lupus, chilblain lupus erythematosus),polymyalgia rheumatica, enthesitis, mixed connective tissue disease,enthesopathy; carditis, myocarditis, angiogenesis disorders,myelodysplastic syndrome, atherosclerosis, restenosis (restenosis of anatherosclerotic coronary artery), acute coronary syndrome, myocardialinfarction, cardiac-allograft vasculopathy, transplant arteriopathy;vasculitis (large vessel vasculitis, small vessel vasculitis, giant-cellarteritis, polyarteritis nodosa, vasculitis syndromes including:Takayasu's arteritis, Wegener's granulomatosis, Behcet's Disease),stimulator of interferon genes (STING) associated vasculopathy withonset in infancy (SAVI); gastrointestinal disorders, enterocolitis,colitis, inflammatory bowel disease (ulcerative colitis, Crohn'sdisease), irritable bowel syndrome, enteritis syndrome/spastic colon,celiac disease; acute and chronic pancreatitis; primary biliarycirrhosis, primary sclerosing cholangitis, jaundice, cirrhosis (forexample, primary biliary cirrhosis or cirrhosis due to fatty liverdisease (for example, alcoholic and nonalcoholic steatosis);esophagitis, gastritis, gastric and duodenal ulcers, peritonitis;Nephropathies: immunologically mediated glomerulonephropathy, autoimmunenephropathy, membranous glomerulopathy, chronic progressivenephropathies, diabetic kidney disease/diabetic nephropathy, renalfibrosis, renal ischemic/reperfusion injury, HIV associated nephropathy,ureteral obstructive nephropathy, glomerulosclerosis, proteinuria,nephrotic syndrome, polycystic kidney disease, autosomal dominantpolycystic kidney disease, a nephropathy is an immunologically mediatednephropathy, autoimmune nephropathy, chronic progressive nephropathies,diabetic nephropathy, renal fibrosis, ischemic/reperfusion injuryassociated, HIV associated nephropathy, ureteral obstructivenephropathy, glomerulonephritis, chronic kidney disease (for example,diabetic nephropathy), hypertension induced nephropathy,glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidneydisease, autosomal dominant polycystic kidney disease, diabetic kidneydisease, lupus nephritis; interstitial cystitis; periodontitis,gingivitis; pulmonary inflammation, sinusitis, pneumonia, bronchitis,asthma, bronchial asthma, allergic asthma, non-allergic asthma, allergicbronchopulmonary mycosis, aspirin-induced asthma, adult-onset asthma,asthma with fixed airflow obstruction, exercise-induced asthma,cough-variant asthma, work-related asthma, nighttime (nocturnal) asthma,asthma with obesity, eosinophilic asthma, steroid-resistantasthma/severe asthma, extrinsic asthma, intrinsic/cryptogenic asthma,Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans, chronicobstructive pulmonary disease (COPD), interstitial lung disease(pulmonary fibrosis, idiopathic pulmonary fibrosis), acute lung injury,pulmonary fibrosis (for example, idiopathic pulmonary fibrosis or cysticfibrosis), chronic obstructive pulmonary disease, adult respiratorydistress syndrome, acute lung injury, drug-induced lung injury;Meniere's disease; ocular disorders including, (e.g.), ocularinflammation, uveitis, dry eye/keratoconjunctivitis sicca, scleritis,episcleritis, keratitis/keratopathy, choroiditis, retinal vasculitis,optic neuritis, retinopathy (diabetic retinopathy, immune mediatedretinopathy, macular degeneration, wet macular degeneration, dry (agerelated) macular degeneration); Mastocytosis, iron deficiency anemia,uremia, hypereosinophilic syndrome (HES), systemic mast cell disease(SMCD), myelodysplastic syndrome, idiopathic thrombocytic purpura; boneresorption diseases; Neurodegenerative disorders,neurological/neuromuscular disorders (e.g.), multiple sclerosis,Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis(ALS) (familial ALS, sporadic ALS), Alzheimer's disease, myastheniagravis, Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barretsyndrome, meningitis, encephalitis, traumatic brain injury; nervoussystem damage, delusional parasitosis, dysregulation of neuronalprocesses and sensory perception, stroke/neuronal ischemia, spinal cordinjury, peripheral neuropathy, tactile hallucinations, spinal cordinjury, psychiatric disease; pain (acute pain, chronic pain, neuropathicpain, or fibromyalgia) paresthetica, nerve irritation, peripheralneuropathy; pruritus/itch (atopic pruritus, xerotic pruritus, pruritusassociated with psoriasis/psoriatic itch/psoriasis-associated itch),acute pruritus, chronic pruritus, idiopathic pruritus, chronicidiopathic itch, biliary itch, hepatobiliary-associated itch, renalassociated itch/renal itch, uremic itch, cholestasis, intrahepaticcholestasis of pregnancy, lichen simplex chronicus associated pruritus,lymphoma-associated itch, leukemia-associated itch, prurigo nodularis,atopic dermatitis-associated itch, atopic itch/atopic pruritus, bullousitch, brachioradial pruritus) neurogenic itch, neuropathic itch,notalgia paresthetica, pruritic popular eruption of HIV, psychogenicitch, swimmer's itch, pruritus or uremic itch, urticarial itch;dermatologic disorders (e.g.), dermatologic drug reactions/drugeruptions, xerosis/dry skin, skin rash, skin sensitization, skinirritation, sunburn, shaving, body louse, head lice/pediculosis, pubiclice, cutaneous larva migrans, scabies, parasitic infection, insectinfestation, urticaria/hives, papular urticaria, insect bites, insectstings, dandruff, foreign objects or devices on skin, fungal infection,herpes, varicella/chicken pox, eosinophilic folliculitis, dermatosis ofpregnancy/pruritic urticarial papules and plaques of pregnancy (PUPP),inflammatory dermatoses, neutrophilic dermatoses, histiocytoidneutrophilic dermatosis, bowel-bypass syndrome dermatosis,psoriasis/psoriasis vulgaris, lichen planus, lichen sclerosus, acne(acne vulgaris, comedonal acne, inflammatory acne, nodulo-cystic acne,scarring acne, acne keloidalis nuchae), atopies (allergic contactsensitization, allergic dermatitis) dermatitis (atopicdermatitis/eczema, contact dermatitis, photodermatitis, seborrheicdermatitis, stasis dermatitis, acute febrile neutrophilic dermatosis(Sweet's syndrome), chronic atypical neutrophilic dermatosis withlipodystrophy and elevated temperature syndrome (CANDLE Syndrome),hidradenitis suppurativa, hives, pyoderma gangrenosum, alopecia (eyebrowalopecia, intranasal hair alopecia, scarring alopecia (e.g., cicatricialalopecia, central centrifugal cicatricial alopecia, lichen planopilaris,frontal fibrosing alopecia, folliculitis decalvans.), nonscarringalopecia (alopecia areata (AA) (patchy AA, alopecia totalis (AT),alopecia universalis (AU), ophiasis pattern alopecia areata, sisaihpopattern alopecia areata)), androgenetic/androgenic alopecia (AGA)/maleand female pattern AGA), telogen effluvium, tinea capitis, hypotrichosis(hereditary hypotrichosis simplex), lichen planopilaris (frontalfibrosing alopecia), punctate palmoplantar keratoderma, erythemaelevatinum diutinum (EED), neutrophilic eccrine hidradenitis, palisadingneutrophilic granulomatous dermatitis, neutrophilic urticarialdermatosis, vitiligo including segmental vitiligo (unisegmentalvitiligo, bisegmental vitiligo, multisegmental vitiligo) non-segmentalvitiligo (acral, facial, or acrofacial vitiligo, centrofacial vitiligo,mucosal vitiligo, confetti vitiligo, trichrome vitiligo, marginalinflammatory vitiligo, quadrichrome vitiligo, blue vitiligo, Koebnerphenomenon, vulgaris vitiligo, generalized vitiligo, universalvitiligo), mixed vitiligo/nonsegmental associated with segmentalvitiligo, focal vitiligo, solitary mucosal vitiligo or vitiligo with orwithout leukotricia (involvement of body hair); bullous diseases,immunobullous diseases (bullous pemphigoid, cicatricial pemphigoid,pemphigus vulgaris, linear IgA disease), gestational pemphigoid,xeroderma pigmentosum; disorders of fibrosis and scarring: fibroids,hepatic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, lowgrade scarring such as, scleroderma, increased fibrosis, keloids,post-surgical scars; wound healing, surgical scarring, radiation inducedfibrosis (for example, head and neck, gastrointestinal or pulmonary),CNS scarring, alimentary track or gastrointestinal fibrosis, renalfibrosis, hepatic or biliary fibrosis, liver fibrosis (for example,nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma),cardiac fibrosis (for example, endomyocardial fibrosis or atrialfibrosis), ophthalmic scarring, fibrosclerosis, scar growth, wound orscab healing, keloid, mediastinal fibrosis, myelofibrosis,retroperitoneal fibrosis/Ormond's disease, progressive massive fibrosis,nephrogenic systemic fibrosis; Sjogren's syndrome, sarcoidosis, familialMediterranean fever, Cryopyrin associated periodic syndrome(Muckle-Wells syndrome, familial cold auto-inflammatorysyndrome/familial cold urticaria/TNF receptor associated periodicsyndrome, neonatal-onset multisystem inflammatory disease), hyperoxiainduced inflammations, reperfusion injury, post-surgical trauma, tissueinjury, elevated temperature syndrome; diabetes (Type I diabetes, TypeII diabetes)/diabetes mellitus, Hashimoto's thyroiditis, Graves'disease, Addison's disease, Castleman's disease, hyperparathyroidism,menopause, obesity, steroid-resistance, glucose intolerance, metabolicsyndrome, thyroid illness, hypophysitis; systemic immune senescence;autoimmune atrophic gastritis, autoimmune atrophic gastritis ofpernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis,Goodpasture's disease, Sjogren's syndrome, autoimmune thrombocytopenia,sympathetic ophthalmia; secondary hematologic manifestations ofautoimmune diseases (for example, anemias), autoimmune hemolyticsyndromes (autoimmune hemolytic anemia), autoimmune and inflammatoryhepatitis, autoimmune ovarian failure, autoimmune thrombocytopenia,silicone implant associated autoimmune disease, drug-inducedautoimmunity, HIV-related autoimmune syndromes, metal-inducedautoimmunity, autoimmune deafness, autoimmune thyroid disorders; allergyand allergic reactions including hypersensitivity reactions such as TypeI hypersensitivity reactions, (e.g. including anaphylaxis), Type IIhypersensitivity reactions (e.g. Goodpasture's Disease, autoimmunehemolytic anemia), Type III hypersensitivity reaction diseases (e.g. theArthus reaction, serum sickness), and Type IV hypersensitivity reactions(e.g. contact dermatitis, allograft rejection); acute and chronicinfection, sepsis syndromes (sepsis, septic shock, endotoxic shock,exotoxin-induced toxic shock, gram negative sepsis, gram positivesepsis, fungal sepsis, toxic shock syndrome); acute and chronicinfection, sepsis syndromes (sepsis, septic shock, endotoxic shock,exotoxin-induced toxic shock, gram negative sepsis, gram positivesepsis, fungal sepsis, toxic shock syndrome); a rejection: graft vs.host reaction/graft vs. host disease, allograft rejections (for example,acute allograft rejection or chronic allograft rejection), earlytransplantation rejection; Malignancy, cancer, lymphoma, leukemia,multiple myeloma, a solid tumor, teratoma, metastatic and bonedisorders, internal cancers, cancer of the: bone, mouth/pharynx,esophagus, larynx, stomach, intestine, colon, rectum, lung (for example,non-small cell lung cancer or small cell lung cancer), liver (hepatic),pancreas, nerve, brain (for example, glioma, glioblastoma multiforme,astrocytoma, neuroblastoma, and schwannomas), head and neck, throat,ovary, uterus, prostate, testis, bladder, kidney (renal), breast, gallbladder, cervix, thyroid, prostate, eye (ocular malignancies), and skin(melanoma, keratoacanthoma); as well as fibrotic cancers, fibroma,fibroadenomas, fibrosarcomas, a myeloproliferative disorder, neoplasm(hematopoietic neoplasm, a myeloid neoplasm, a lymphoid neoplasm(myelofibrosis, primary myelofibrosis, polycythemia vera, essentialthrombocythemia)), leukemias (acute lymphocytic leukemia, acute andchronic myelogenous leukemia, chronic lymphocytic leukemia, acutelymphoblastic leukemia, chronic myelomonocytic leukemia (CMML), orpromyelocytic leukemia), multiple myeloma and other myeloid malignancies(myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis(PMF), idiopathic myelofibrosis (IMF)), lymphomas (Hodgkin's disease,cutaneous lymphomas (cutaneous T-cell lymphoma, mycosis fungoides),lymphomas (for example, B-cell lymphoma, T-cell lymphoma, mantle celllymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumors,Hodgkin's disease or non-Hodgkin's disease); Kaposi's sarcoma,rhabdomyosarcoma, seminoma, teratocarcinoma, osteosarcoma, thyroidfollicular cancer; increased accumulation of exogenous opioids orsynthetic opioids, notalgia paraesthetica, obsessive-compulsivedisorders, nostalgia associated with obsessive-compulsive disorders, anda combination thereof.
 12. The method of claim 10, wherein the othertherapeutic agent is selected from a chemotherapeutic agent, ananti-proliferative agent, an anti-inflammatory agent, animmunomodulatory agent, immunosuppressive agent, a neurotrophic factor,an agent for treating cardiovascular disease, an agent for treatingdiabetes, an agent for treating immunodeficiency disorders, and acombination thereof.
 13. The method of claim 11, wherein saidJAK-mediated disease is inflammatory bowel disease.
 14. The method ofclaim 13, wherein upon said administering the compound inhibits JAKactivity in a gut-restricted manner in said subject.